13-20189546-AC-ACC
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_004004.6(GJB2):c.35dupG(p.Val13CysfsTer35) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_004004.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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GJB2 | ENST00000382848.5 | c.35dupG | p.Val13CysfsTer35 | frameshift_variant | Exon 2 of 2 | 1 | NM_004004.6 | ENSP00000372299.4 | ||
GJB2 | ENST00000382844.2 | c.35dupG | p.Val13CysfsTer35 | frameshift_variant | Exon 1 of 1 | 6 | ENSP00000372295.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249362Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 134954
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461606Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727100
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:7
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This sequence change creates a premature translational stop signal (p.Val13Cysfs*35) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 214 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs398123814, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive deafness (PMID: 11439000, 18519481, 19366456, 20497192, 23638949, 24503448). It has also been observed to segregate with disease in related individuals. This variant is also known as 35insG. ClinVar contains an entry for this variant (Variation ID: 94392). For these reasons, this variant has been classified as Pathogenic. -
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Frameshift variant predicted to result in protein truncation, as the last 214 amino acids are replaced with 34 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 9482292, 29754767, 31589614, 31541171, 29871260, 32645618, 31160754, 34416374, 23638949, 20639189, 24503448) -
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) In multiple individuals with nonsyndromic hearing loss, this variant has been seen with a single recessive pathogenic variant in the same gene. In some published literature, this variant is referred to as c.35insG. -
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:5
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Variant summary: GJB2 c.35dupG (p.Val13CysfsX35) results in a premature termination codon, predicted to cause a truncation, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.4e-05 in 249362 control chromosomes (gnomAD). c.35dupG has been reported in the literature in several individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (e.g. Rabionet_2000, D'Andrea_2002, Dai_2009, Hjelm_2010, Godbole_2010, Bazazzadegan_2012, Usami_2012, Banjara_2015, Liu_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
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Hearing loss Pathogenic:1
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Hearing impairment Pathogenic:1
PVS1_Strong, PM2_Moderate, BP5_Supporting -
Rare genetic deafness Pathogenic:1
The p.Val13fs variant in GJB2, also reported as c.35dupG or c.35insG, has been r eported in >5 individuals with hearing loss who were compound heterozygous for a second pathogenic variant in GJB2 (Estivill 1998, Huang 2014, Snoeckx 2005, Tsu kada 2010). It has been identified in 6/250260 of the total chromosomes in the genome Aggregation Database (http://gnomad.broadinstitute.org/, dbSNP rs39812381 4). This low frequency in the general population is consistent with the carrier frequency for autosomal recessive hearing loss. This variant is predicted to ca use a frameshift, which alters the protein?s amino acid sequence beginning at po sition 13 and leads to a premature termination codon 35 amino acids downstream. In summary, this variant meets criteria to be classified as pathogenic for autos omal recessive hearing loss based on the predicted impact to the protein and mul tiple previously reported affected compound heterozygotes. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at