13-20189068-A-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM5PP5
The NM_004004.6(GJB2):c.514T>A(p.Trp172Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,776 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W172C) has been classified as Pathogenic.
Frequency
Consequence
NM_004004.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.514T>A | p.Trp172Arg | missense_variant | 2/2 | ENST00000382848.5 | |
GJB2 | XM_011535049.3 | c.514T>A | p.Trp172Arg | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.514T>A | p.Trp172Arg | missense_variant | 2/2 | 1 | NM_004004.6 | P1 | |
GJB2 | ENST00000382844.2 | c.514T>A | p.Trp172Arg | missense_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251118Hom.: 1 AF XY: 0.00000737 AC XY: 1AN XY: 135748
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461776Hom.: 1 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727182
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 05, 2023 | This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 172 of the GJB2 protein (p.Trp172Arg). This variant is present in population databases (rs770330002, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 18941476). ClinVar contains an entry for this variant (Variation ID: 557805). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB2 protein function. Experimental studies have shown that this missense change affects GJB2 function (PMID: 18941476). This variant disrupts the p.Trp172 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15790391, 20201936, 31195736). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 06, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at