ClinVar Genomic variation as it relates to human health
NM_012275.3(IL36RN):c.115+6T>C
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(3); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_012275.3(IL36RN):c.115+6T>C
Variation ID: 40005 Accession: VCV000040005.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q14.1 2: 113060943 (GRCh38) [ NCBI UCSC ] 2: 113818520 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 28, 2014 Mar 16, 2024 Feb 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_012275.3:c.115+6T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_173170.1:c.115+6T>C intron variant NC_000002.12:g.113060943T>C NC_000002.11:g.113818520T>C NG_031864.1:g.7306T>C LRG_730:g.7306T>C LRG_730t1:c.115+6T>C LRG_730t2:c.115+6T>C - Protein change
- Other names
- IVS3, T-C, +6
- Canonical SPDI
- NC_000002.12:113060942:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00280 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00100
Exome Aggregation Consortium (ExAC) 0.00101
1000 Genomes Project 30x 0.00219
1000 Genomes Project 0.00280
The Genome Aggregation Database (gnomAD) 0.00021
Trans-Omics for Precision Medicine (TOPMed) 0.00065
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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IL36RN | - | - |
GRCh38 GRCh37 |
190 | 213 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Dec 30, 2023 | RCV000033132.21 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 12, 2016 | RCV002262597.3 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 24, 2023 | RCV002508136.5 | |
IL36RN-related disorder
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Likely pathogenic (1) |
criteria provided, single submitter
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Feb 16, 2024 | RCV003914894.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Dec 12, 2016)
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criteria provided, single submitter
Method: clinical testing
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Autoinflammatory syndrome
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002543472.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
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Pathogenic
(Dec 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Acrodermatitis continua suppurativa of Hallopeau
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023156.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Acrodermatitis continua suppurativa of Hallopeau
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001288877.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Likely pathogenic
(Feb 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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Acrodermatitis continua suppurativa of Hallopeau
Affected status: yes
Allele origin:
germline
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Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital
Accession: SCV001739494.1
First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Ethnicity/Population group: East asia
Geographic origin: China
Testing laboratory: Liwei's Lab
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Pathogenic
(Mar 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Acrodermatitis continua suppurativa of Hallopeau
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001135931.2
First in ClinVar: Jan 13, 2020 Last updated: Mar 26, 2023 |
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Pathogenic
(Dec 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Generalized pustular psoriasis
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000949734.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 3 of the IL36RN gene. It does not directly change the encoded amino acid sequence of the IL36RN protein. … (more)
This sequence change falls in intron 3 of the IL36RN gene. It does not directly change the encoded amino acid sequence of the IL36RN protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs148755083, gnomAD 1.3%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with generalized pustular psoriasis (PMID: 22903787, 23303454, 23698098, 23863864, 24979538, 26589685, 28063630). It is commonly reported in individuals of Japanese and Chinese ancestry (PMID: 22903787, 23303454, 23698098, 23863864, 24979538, 26589685, 28063630). ClinVar contains an entry for this variant (Variation ID: 40005). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3 and introduces a premature termination codon (PMID: 22903787, 23698098). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Feb 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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IL36RN-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004742886.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The IL36RN c.115+6T>C variant is predicted to interfere with splicing. RNA studies have shown this variant leads to skipping of exon 3 (Farooq et al. … (more)
The IL36RN c.115+6T>C variant is predicted to interfere with splicing. RNA studies have shown this variant leads to skipping of exon 3 (Farooq et al. 2013. PubMed ID: 22903787). This variant, in the compound heterozygous and homozygous states, has been reported to be associated with generalized pustular psoriasis with incomplete penetrance (Sugiura et al. 2012. PubMed: 23303454; Shiratori et al. 2015. PubMed ID: 25615897; Liang et al. 2017. PubMed ID: 27900482; Setta-Kaffetzi et al. 2013. PubMed ID: 23303454). This variant is reported in 1.3% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic. (less)
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Pathogenic
(Nov 01, 2013)
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no assertion criteria provided
Method: literature only
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PSORIASIS 14, PUSTULAR
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000056913.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 28, 2014 |
Comment on evidence:
In a 76-year-old Japanese man and an unrelated 17-year-old Japanese boy with generalized pustular psoriasis (PSORS14; 614204), Farooq et al. (2013) identified compound heterozygosity for … (more)
In a 76-year-old Japanese man and an unrelated 17-year-old Japanese boy with generalized pustular psoriasis (PSORS14; 614204), Farooq et al. (2013) identified compound heterozygosity for a T-C transition in intron 3 (c.115+6C-T) of the IL36RN gene, and a missense or a nonsense mutation, respectively: the man carried a c.368C-G transversion in exon 5, resulting in a thr123-to-arg (T123R; 605507.0005) substitution at an evolutionarily conserved residue, whereas the boy carried a 28C-T transition in exon 2, resulting in an arg10-to-ter (R10X; 605507.0006) substitution. Expression analysis of total RNA from the patients' skin demonstrated that the intronic mutation causes skipping of exon 3, resulting in a frameshift and an immediate premature termination codon (Arg10ArgRfsTer1). Functional analysis in HEK293T cells showed that the T123R mutant was expressed at a much lower level than wildtype and failed to antagonize the IL36 signaling pathway. Farooq et al. (2013) noted that the R10X mutation had previously been identified in homozygosity in a Japanese patient with GPP (Sugiura et al., 2012), and suggested that both the 115+6T-C and R10X mutations might be common founder mutations in the Japanese population. In 2 Chinese and 2 Malay patients with GPP, Setta-Kaffetzi et al. (2013) identified homozygosity for the c.115+6T-C mutation in IL36RN. In addition, 1 Malay patient with GPP was compound heterozygous for both c.115+6T-C and the S113L substitution in IL36RN (605507.0002). In 2 Chinese and 3 Malay patients with GPP, only a heterozygous c.115+6T-C mutation was detected in IL36RN. In a study of 68 Chinese patients with GPP, 113 with PV, and 373 controls, Li et al. (2013) observed that c.115+6T-C was the most common mutation in GPP but that there was no significant association with PV. The mutation was also present in 3.6% of controls, and was detected in homozygosity in 2 healthy controls who were more than 40 years old. Li et al. (2013) concluded that multiple factors contribute to the pathogenesis of GPP. (less)
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Pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Pustular psoriasis, generalized
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142321.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
NG_031864.1(NM_012275.2):c.115+6T>C in the IL36RN gene has an allele frequency of 0.013 in East Asian subpopulation in the gnomAD database. Farooq M et al. reported one … (more)
NG_031864.1(NM_012275.2):c.115+6T>C in the IL36RN gene has an allele frequency of 0.013 in East Asian subpopulation in the gnomAD database. Farooq M et al. reported one patient with generalized pustular psoriasis was compound heterozygous for mutations c.115+6T>C and c.368C>G (p.Thr123Arg) and another was compound heterozygous for mutations c.28C>T (p.Arg10*) and c.115+6T>C in the IL36RN gene (PMID: 22903787). Shu D et al. reported two siblings with deficiency of IL-36Ra, from a Chinese Daur family, who both carried the homozygous IL36RN c.115+6T>C mutation, while other four healthy family members carried heterozygous c.115+6T>C mutations (PMID: 24979538). Experimental studies have shown that this intronic change causes skipping of exon 3, resulting in a truncated protein product (PMID: 23698098; 22903787). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3_Strong, PP1, PP4. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical profiles of pediatric patients with GPP alone and with different IL36RN genotypes. | Wang Y | Journal of dermatological science | 2017 | PMID: 28063630 |
Correlation of IL36RN mutation with different clinical features of pustular psoriasis in Chinese patients. | Wang TS | Archives of dermatological research | 2016 | PMID: 26589685 |
Mutation analysis of IL36RN in a Chinese Daur family with generalized pustular psoriasis. | Shu D | European journal of dermatology : EJD | 2014 | PMID: 24979538 |
Prevalent and rare mutations in IL-36RN gene in Chinese patients with generalized pustular psoriasis and psoriasis vulgaris. | Li M | The Journal of investigative dermatology | 2013 | PMID: 23863864 |
The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist. | Sugiura K | The Journal of investigative dermatology | 2013 | PMID: 23698098 |
Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes. | Setta-Kaffetzi N | The Journal of investigative dermatology | 2013 | PMID: 23303454 |
Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis. | Farooq M | Human mutation | 2013 | PMID: 22903787 |
A novel IL36RN/IL1F5 homozygous nonsense mutation, p.Arg10X, in a Japanese patient with adult-onset generalized pustular psoriasis. | Sugiura K | The British journal of dermatology | 2012 | PMID: 22428995 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs148755083 ...
HelpRecord last updated May 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.