ClinVar Genomic variation as it relates to human health
NM_002485.5(NBN):c.1880A>G (p.Lys627Arg)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002485.5(NBN):c.1880A>G (p.Lys627Arg)
Variation ID: 230646 Accession: VCV000230646.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q21.3 8: 89947858 (GRCh38) [ NCBI UCSC ] 8: 90960086 (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 May 29, 2016 May 1, 2024 Sep 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002485.5:c.1880A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002476.2:p.Lys627Arg missense NM_001024688.3:c.1634A>G NP_001019859.1:p.Lys545Arg missense NC_000008.11:g.89947858T>C NC_000008.10:g.90960086T>C NG_008860.1:g.41814A>G LRG_158:g.41814A>G LRG_158t1:c.1880A>G LRG_158p1:p.Lys627Arg - Protein change
- K627R, K545R
- Other names
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- Canonical SPDI
- NC_000008.11:89947857: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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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NBN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3381 | 3553 | |
LOC126860438 | - | - | - | GRCh38 | - | 145 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Mar 15, 2022 | RCV000214447.7 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Sep 23, 2023 | RCV000232800.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 10, 2022 | RCV002272179.4 |
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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Uncertain significance
(Jan 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002558246.2
First in ClinVar: Aug 08, 2022 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In a … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In a breast cancer case control study, this variant was absent in cases but present in controls (Momozawa 2018); This variant is associated with the following publications: (PMID: 30287823) (less)
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Uncertain significance
(Jun 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003813489.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Mar 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000274268.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.K627R variant (also known as c.1880A>G), located in coding exon 12 of the NBN gene, results from an A to G substitution at nucleotide … (more)
The p.K627R variant (also known as c.1880A>G), located in coding exon 12 of the NBN gene, results from an A to G substitution at nucleotide position 1880. The lysine at codon 627 is replaced by arginine, an amino acid with highly similar properties. This alteration was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0001 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jul 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001349307.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
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Uncertain significance
(Nov 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly, normal intelligence and immunodeficiency
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002044523.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Uncertain significance
(Sep 30, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002536623.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
To the best of our knowledge, the NBN c.1880A>G (p.K627R) variant has not been reported in individuals with NBN-related disease. This variant was observed in … (more)
To the best of our knowledge, the NBN c.1880A>G (p.K627R) variant has not been reported in individuals with NBN-related disease. This variant was observed in 1/103462 chromosomes in the Non-Finnish European population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 230646). In silico tools suggest the impact of the variant on protein function is benign, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Sep 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly, normal intelligence and immunodeficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000287456.7
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 627 of the NBN protein (p.Lys627Arg). … (more)
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 627 of the NBN protein (p.Lys627Arg). This variant is present in population databases (rs762174459, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 230646). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Aug 03, 2021)
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no assertion criteria provided
Method: clinical testing
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Nijmegen breakage syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002078530.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Text-mined citations for rs762174459 ...
HelpRecord last updated May 08, 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.