chr13-20189503-C-T
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Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1
The NM_004004.6(GJB2):c.79G>A(p.Val27Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0184 in 1,614,144 control chromosomes in the GnomAD database, including 4,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.026 ( 418 hom., cov: 32)
Exomes 𝑓: 0.018 ( 3603 hom. )
Consequence
GJB2
NM_004004.6 missense
NM_004004.6 missense
Scores
1
8
8
Clinical Significance
Conservation
PhyloP100: 6.12
Genes affected
GJB2 (HGNC:4284): (gap junction protein beta 2) This gene encodes a member of the gap junction protein family. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -18 ACMG points.
PM1
?
In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004004.6
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0041432083).
BP6
?
Variant 13-20189503-C-T is Benign according to our data. Variant chr13-20189503-C-T is described in ClinVar as [Benign]. Clinvar id is 36279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189503-C-T is described in Lovd as [Likely_benign]. Variant chr13-20189503-C-T is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.79G>A | p.Val27Ile | missense_variant | 2/2 | ENST00000382848.5 | |
GJB2 | XM_011535049.3 | c.79G>A | p.Val27Ile | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.79G>A | p.Val27Ile | missense_variant | 2/2 | 1 | NM_004004.6 | P1 | |
GJB2 | ENST00000382844.2 | c.79G>A | p.Val27Ile | missense_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0259 AC: 3943AN: 152180Hom.: 419 Cov.: 32
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GnomAD3 exomes AF: 0.0540 AC: 13514AN: 250230Hom.: 1750 AF XY: 0.0444 AC XY: 6013AN XY: 135380
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GnomAD4 exome AF: 0.0176 AC: 25688AN: 1461846Hom.: 3603 Cov.: 33 AF XY: 0.0164 AC XY: 11950AN XY: 727222
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GnomAD4 genome ? AF: 0.0259 AC: 3949AN: 152298Hom.: 418 Cov.: 32 AF XY: 0.0308 AC XY: 2293AN XY: 74480
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ClinVar
Significance: Benign
Submissions summary: Benign:20
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:7
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 30, 2015 | 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. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 09, 2011 | Val27Ile in exon 2 of GJB2: This variant is benign based on its high frequency i n the general population (rs2274084) with a homozygous frequency of 12-20% in th e Asian population. - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 14, 2014 | - - |
Autosomal recessive nonsyndromic hearing loss 1A Benign:5
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Pars Genome Lab | Jul 01, 2021 | - - |
Benign, no assertion criteria provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 31, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | May 09, 2017 | - - |
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 11, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Autosomal dominant nonsyndromic hearing loss 3A Benign:2
Benign, criteria provided, single submitter | clinical testing | Pars Genome Lab | Jul 01, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Ichthyosis, hystrix-like, with hearing loss Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Benign:1
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 25, 2017 | - - |
Nonsyndromic genetic hearing loss Benign:1
Benign, criteria provided, single submitter | clinical testing | INGEBI, INGEBI / CONICET | Aug 31, 2020 | Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of c.79G>A variant (p.Val27Ile) in GJB2 gene is 27,2% (5547/ 19950 East Asian alleles with 95% CI), 21,7% in Latino population and 4,97% in all ethnic groups from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering very strong evidence against pathogenicity for autosomal recessive hearing loss variants (BA1). The c.79G>A variant has been detected in high frequency in control individuals among different population (PMID: 10633133, 10983956, 15504600, 23503914, 24645897). This variant has been found in cis with pathogenic variants, applying to BP2 (PMID: 24158611). Besides, functional studies showed that p.Val27Ile mutant generated electrical conductance equal to wild type between paired Xenopus laevis oocytes. The same result was obtained when p.Val27Ile mutant was co-injected to hWtCX30, (PMID: 16300957; BS3_Supporting). In summary, this variant meets criteria to be classified as benign for autosomal recessive non-syndromic hearing loss BA1, BP2 and BS3_Supporting. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M
MutationTaster
Benign
P;P
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.
REVEL
Uncertain
Sift
Benign
T;T;.
Sift4G
Benign
T;T;.
Polyphen
D;D;D
Vest4
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at