rs767178508
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_004004.6(GJB2):c.439G>A(p.Glu147Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E147G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004004.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.439G>A | p.Glu147Lys | missense_variant | 2/2 | ENST00000382848.5 | |
GJB2 | XM_011535049.3 | c.439G>A | p.Glu147Lys | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.439G>A | p.Glu147Lys | missense_variant | 2/2 | 1 | NM_004004.6 | P1 | |
GJB2 | ENST00000382844.2 | c.439G>A | p.Glu147Lys | missense_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251014Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135742
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461794Hom.: 0 Cov.: 33 AF XY: 0.0000344 AC XY: 25AN XY: 727182
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74340
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 18, 2016 | - - |
Likely pathogenic, no assertion criteria provided | case-control | Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital | Feb 26, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Aug 04, 2017 | A heterozygous missense variant was identified, NM_004004.5(GJB2):c.439G>A in exon 2 of the GJB2 gene. This substitution creates a minor amino acid change from a glutamic acid to a lysine at position 147, NP_003995.2(GJB2):p.(Glu147Lys). The glutamic acid at this position has very high conservation (100 vertebrates, UCSC) and in silico predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster).This variant is present in the gnomAD population database at a frequency of 0.001% and it has been previously reported in patients with autosomal recessive deafness (ClinVar, Frei, K. et al. (2004) and Cryns, K. et al. (2004)).It is situated in the third transmembrane domain, which has been shown to be essential for protein function (Frei K. et al. (2004). Based on current information and in association with the NM_004004.5(GJB2):c.35delG deletion variant, this variant has been classified as PATHOGENIC.The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with autosomal recessive deafness. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 147 of the GJB2 protein (p.Glu147Lys). This variant is present in population databases (rs767178508, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 14676473, 21465647, 30168495, 30344259). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 371709). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 18, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15253766, 26188157, 25149764, 29921236, 30168495, 29542069, 14676473, 19371219, 14985372, 16380907, 16125251, 17567887, 20022641, 21465647, 26346709, 25388846, 26043044, 30094485, 31215297, 30989077, 30344259, 21131880, 31160754, 30275481, 32645618, 33096615, 31589614, 29871260, 31541171, 31827275) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2019 | - - |
Nonsyndromic genetic hearing loss Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | INGEBI, INGEBI / CONICET | Aug 21, 2020 | Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.439G>A, p.(Glu147Lys) was observed only once in South Asian, Latino and European non-Finnish populations from Genome Aggregation Database (http://gnomad.broadinstitute.org), meeting PM2 criteria. This was detected in trans with at least 4 different pathogenic variants applying to PM3_VeryStrong rule (PMID: 14676473, 21131880, 14985372, 21465647, 26043044). Besides, it segregated in three affected siblings with congenital moderate-profound hearing loss meeting PP1_Moderate criteria (PMID:14676473). Computational evidence predicted a damage impact of the mutation to the protein (REVEL score: 0,94; PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2, PM3_VeryStrong, PP1_Moderate and PP3. - |
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | May 11, 2022 | - - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 15, 2016 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 21, 2018 | The p.Glu147Lys variant in GJB2 has been reported in 8 individuals with hearing loss, including 3 homozygotes and 5 individuals who were compound heterozygous f or a second pathogenic variant (Cryns 2004, de Oliveira 2007, Dodson 2011, Frei 2004, Gravina 2010, Lin 2011, Snoeckx 2005, Zheng 2015). In addition, the varian t segregated in the homozygous state in two affected siblings in one family (Fre i 2004). This variant is present in 3/245794 total chromosomes by gnomAD (http:/ /gnomad.broadinstitute.org), which is low enough to be consistent with a recessi ve carrier frequency. Computational prediction tools and conservation analysis s uggest an impact to the protein. In summary, this variant meets criteria to be c lassified as pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3_VeryStrong, PM2, PP1_Moderate, PP3. - |
Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 18, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at