rs397516873
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_004004.6(GJB2):βc.31_68delβ(p.Gly11LeufsTer24) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. G11G) has been classified as Likely benign.
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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.31_68del | p.Gly11LeufsTer24 | frameshift_variant | 2/2 | ENST00000382848.5 | |
GJB2 | XM_011535049.3 | c.31_68del | p.Gly11LeufsTer24 | frameshift_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.31_68del | p.Gly11LeufsTer24 | frameshift_variant | 2/2 | 1 | NM_004004.6 | P1 | |
GJB2 | ENST00000382844.2 | c.31_68del | p.Gly11LeufsTer24 | frameshift_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250064Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135304
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461870Hom.: 0 AF XY: 0.0000193 AC XY: 14AN XY: 727234
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74366
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change creates a premature translational stop signal (p.Gly11Leufs*24) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 216 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs397516873, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 9336442, 12189487, 16380907, 21465647, 25214170). This variant is also known as 31del38. ClinVar contains an entry for this variant (Variation ID: 44738). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Leu213*) have been determined to be pathogenic (PMID: 23141775). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 18, 2018 | The c.31_68del38 variant in the GJB2 gene has been reported previously in association with hearing loss (Snoeckx et al., 2005; Dodson et al., 2011; Beck et al., 2014). The deletion causes a frameshift starting with codon Glycine 11, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 24 of the new reading frame, denoted p.Gly11LeufsX24. This variant is predicted to cause loss of normal protein function through protein truncation. The variant is observed in 5/110262 (0.0045%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 24, 2020 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Mar 14, 2016 | - - |
Nonsyndromic genetic hearing loss Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 09, 2021 | Variant summary: GJB2 c.31_68del38 (p.Gly11LeufsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 250064 control chromosomes. c.31_68del38 has been reported in the literature in multiple individuals affected with Non-Syndromic Hearing Loss (e.g. Denoyelle_1997, Janecke_2002, Dodson_2011, Beck_2015). 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. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
GJB2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 05, 2024 | The GJB2 c.31_68del38 variant is predicted to result in a frameshift and premature protein termination (p.Gly11Leufs*24). This variant was reported in several individuals with autosomal recessive deafness (Denoyelle et al. 1997. PubMed ID: 9336442; Dodson et al. 2011. PubMed ID: 21465647; Tang et al. 2006. PubMed ID: 17041943; and several other reports). This variant is reported in 0.0045% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in GJB2 are expected to be pathogenic and this variant has been consistently classified as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/44738/). This variant is interpreted as pathogenic. - |
Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 14, 2016 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 17, 2012 | The Gly11fs variant in GJB2 has been reported in one individual with hearing los s (Denoyelle 1997). This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 11 and lead to a premature termination codon 24 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at