chr13-20189395-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP3_StrongPP5
The NM_004004.6(GJB2):c.187G>A(p.Val63Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,260 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V63A) has been classified as Uncertain significance.
Frequency
Consequence
NM_004004.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.187G>A | p.Val63Met | missense_variant | 2/2 | ENST00000382848.5 | |
GJB2 | XM_011535049.3 | c.187G>A | p.Val63Met | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.187G>A | p.Val63Met | missense_variant | 2/2 | 1 | NM_004004.6 | P1 | |
GJB2 | ENST00000382844.2 | c.187G>A | p.Val63Met | missense_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152198Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251252Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135776
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461062Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 726662
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152198Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74360
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 05, 2013 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 63 of the GJB2 protein (p.Val63Met). This variant is present in population databases (rs370696868, gnomAD 0.004%). This missense change has been observed in individual(s) with deafness (PMID: 14985372, 17666888, 21366436, 26252218). ClinVar contains an entry for this variant (Variation ID: 94391). 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. This variant disrupts the p.Val63 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17041943; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at