rs780320724
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
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
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
GJB6
NM_001110219.3 missense
NM_001110219.3 missense
Scores
9
9
1
Clinical Significance
Conservation
PhyloP100: 9.70
Genes affected
GJB6 (HGNC:4288): (gap junction protein beta 6) Gap junctions allow the transport of ions and metabolites between the cytoplasm of adjacent cells. They are formed by two hemichannels, made up of six connexin proteins assembled in groups. Each connexin protein has four transmembrane segments, two extracellular loops, a cytoplasmic loop formed between the two inner transmembrane segments, and the N- and C-terminus both being in the cytoplasm. The specificity of the gap junction is determined by which connexin proteins comprise the hemichannel. In the past, connexin protein names were based on their molecular weight, however the new nomenclature uses sequential numbers based on which form (alpha or beta) of the gap junction is present. This gene encodes one of the connexin proteins. Mutations in this gene have been found in some forms of deafness and in some families with hidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB6 | NM_001110219.3 | c.119C>T | p.Ala40Val | missense_variant | 5/5 | ENST00000647029.1 | NP_001103689.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GJB6 | ENST00000647029.1 | c.119C>T | p.Ala40Val | missense_variant | 5/5 | NM_001110219.3 | ENSP00000493834 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251494Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135922
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727238
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 06, 2022 | 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. - |
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:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2022 | 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GJB6 function (PMID: 21731760, 22617145). 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. ClinVar contains an entry for this variant (Variation ID: 424855). This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 17259707). This variant is present in population databases (rs780320724, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. 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). - |
Autosomal dominant nonsyndromic hearing loss 3B Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;.;.;.;.;.;.;.;.;.;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;M;M;M;M;M;M;M;M;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;D;.;.;D;.;.;.;.;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;.;D;D;.;.;D;.;.;.;.;.;.;.;.
Sift4G
Uncertain
D;.;D;D;.;.;D;.;.;.;.;.;.;.;.
Polyphen
D;D;D;D;D;D;D;D;D;D;D;.;.;.;.
Vest4
MutPred
Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);
MVP
MPC
0.49
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Score
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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