chr13-20223362-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2PP3_StrongBS1_Supporting
The NM_001110219.3(GJB6):c.119C>T(p.Ala40Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,872 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 Uncertain significance (★★).
Frequency
Consequence
NM_001110219.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB6 | NM_001110219.3 | c.119C>T | p.Ala40Val | missense_variant | Exon 5 of 5 | ENST00000647029.1 | NP_001103689.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251494Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135922
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727238
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hidrotic ectodermal dysplasia syndrome;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B;C2675237:Autosomal dominant nonsyndromic hearing loss 3B Uncertain:2
PP3 -
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 40 of the GJB6 protein (p.Ala40Val). This variant is present in population databases (rs780320724, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 17259707). ClinVar contains an entry for this variant (Variation ID: 424855). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GJB6 function (PMID: 21731760, 22617145). -
not specified Uncertain:1
Variant summary: GJB6 c.119C>T (p.Ala40Val) results in a non-conservative amino acid change located in the first transmembrane domain (Yang_2010) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251494 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.00076 in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4800-fold of the estimated maximal expected allele frequency for a pathogenic variant in GJB6 causing Hidrotic Ectodermal Dysplasia Syndrome phenotype (1.6e-07), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. On the other hand, the variant c.119C>T has been reported in the literature in individuals affected with nonsyndromic hearing-loss (Yang_2010, Oh_2013). The authors of these reports also performed in vitro functional studies evaluating an impact on protein function, and one of these demonstrated that the A40V variant protein resulted in CX30 protein accumulation in the Golgi rather than in the cytoplasmic membrane (Wang_2011), while the other study demonstrated proper localization and function for the variant protein (Oh_2013). These data do not allow clear conclusions about variant significance. Two submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=1) and VUS (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Autosomal dominant nonsyndromic hearing loss 3B Other:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at