NM_004004.6(GJB2):c.-45C>A AND not specified

Clinical significance:Benign/Likely benign (Last evaluated: Aug 11, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000037808.8

Allele description [Variation Report for NM_004004.6(GJB2):c.-45C>A]

NM_004004.6(GJB2):c.-45C>A

Gene:
GJB2:gap junction protein beta 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
13q12.11
Genomic location:
Preferred name:
NM_004004.6(GJB2):c.-45C>A
HGVS:
  • NC_000013.11:g.20192805G>T
  • NG_008358.1:g.5171C>A
  • NM_004004.6:c.-45C>AMANE SELECT
  • LRG_1350t1:c.-45C>A
  • LRG_1350:g.5171C>A
  • NC_000013.10:g.20766944G>T
  • NM_004004.5:c.-45C>A
  • c.-45C>A
Links:
dbSNP: rs397516868
NCBI 1000 Genomes Browser:
rs397516868
Molecular consequence:
  • NM_004004.6:c.-45C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
Observations:
14

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000061470Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Benign
(Jun 13, 2017)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000698259Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Benign
(Aug 11, 2021)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000724451GeneDxcriteria provided, single submitter
Likely benign
(Oct 31, 2017)
germlineclinical testing

Citation Link,

SCV000841709Athena Diagnostics Inccriteria provided, single submitter
Likely benign
(Feb 10, 2021)
unknownclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001955484Human Genetics - Radboudumc,Radboudumc - VKGL Data-share Consensus

See additional submitters

no assertion criteria providedBenigngermlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided1414not providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

[Changes in the connexin 26 (GJB2) gene in Russian patients with hearing disorders: results of long-term molecular diagnostics of hereditary nonsyndromic deafness].

Bliznets EA, Galkina VA, Matiushchenko GN, Kisina AG, Markova TG, Poliakov AV.

Genetika. 2012 Jan;48(1):112-24. Russian.

PubMed [citation]
PMID:
22567861
See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000061470.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided14not providednot providedclinical testing PubMed (4)

Description

c.-45C>A in Exon 1 of GJB2: This variant has been identified in 0.4%(58/14946) o f European chromosomes by the Genome Aggregation Database (gnomAD; http://gnoma d.broadinstitute.org; dbSNP rs397516868). Expression studies showed presence of the expressed GJB2 gene (Wilch 2006).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided14not provided14not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698259.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: GJB2 c.-45C>A is located in the untranslated mRNA region upstream of the initiation codon. One in silico tool predicts a benign outcome for this variant. The variant allele was found at a frequency of 0.0024 in 31410 control chromosomes, predominantly at a frequency of 0.0039 within the Non-Finnish European subpopulation in the gnomAD database (genomes). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss phenotype (0.00034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.-45C>A, has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss but was also found in controls (Matos_2011). In addition, multiple publications classify the variant as polymorphism (Wilch_2006, Bliznets_2012, Beck_2014), which is supported by the evidence that the variant was observed in trans with a pathogenic allele in an unaffected individual, suggesting a lack of segregation with disease. An allele-based expression analysis showed presence of the expressed GJB2 gene (Wilch_2006) demonstrating no damaging effect of this variant. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely benign (n=2) and benign (n=1). Based on the evidence outlined above, the variant was classified as benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From GeneDx, SCV000724451.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Athena Diagnostics Inc, SCV000841709.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Human Genetics - Radboudumc,Radboudumc - VKGL Data-share Consensus, SCV001955484.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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