13-20189450-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_004004.6(GJB2):c.132G>A(p.Trp44Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,176 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000022 ( 0 hom. )
Consequence
GJB2
NM_004004.6 stop_gained
NM_004004.6 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 7.85
Genes affected
GJB2 (HGNC:4284): (gap junction protein beta 2) This gene encodes a member of the gap junction protein family. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 208 pathogenic variants in the truncated region.
PP5
?
Variant 13-20189450-C-T is Pathogenic according to our data. Variant chr13-20189450-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 158605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189450-C-T is described in Lovd as [Pathogenic]. Variant chr13-20189450-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.132G>A | p.Trp44Ter | stop_gained | 2/2 | ENST00000382848.5 | |
GJB2 | XM_011535049.3 | c.132G>A | p.Trp44Ter | stop_gained | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.132G>A | p.Trp44Ter | stop_gained | 2/2 | 1 | NM_004004.6 | P1 | |
GJB2 | ENST00000382844.2 | c.132G>A | p.Trp44Ter | stop_gained | 1/1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152174Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250944Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135638
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GnomAD4 exome AF: 0.0000219 AC: 32AN: 1460884Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 726532
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Genomics and Human Genetics Laboratory, Pasteur Institut of Morocco | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 24, 2021 | Variant summary: GJB2 c.132G>A (p.Trp44X) 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 3.5e-05 in 258564 control chromosomes. c.132G>A has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (example, Green_1999, Prasad_2000, Snoeckx_2005, Roux_2004, Tang_2006, Putcha_2007, Lin_2011). 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Mar 06, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 09, 2017 | The GJB2 c.132G>A; p.Trp44Ter variant (rs104894407) has been reported in the literature in individuals with hearing loss who carried a pathogenic variant on the opposite chromosome (Green 1999, Martinez-Saucedo 2015, Roux 2004). It is reported in ClinVar (Variation ID: 158605), and observed in the general population databases at a frequency of 0.003 percent (8/276604 alleles; Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript, and is considered pathogenic. REFERENCES Link to ClinVar database for p.Trp44Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/158605/ Green GE et al. Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. JAMA. 1999 Jun 16;281(23):2211-6. Martinez-Saucedo M et al. Two novel compound heterozygous families with a trimutation in the GJB2 gene causing sensorineural hearing loss. Int J Pediatr Otorhinolaryngol. 2015 Dec;79(12):2295-9. Roux AF et al. Molecular epidemiology of DFNB1 deafness in France. BMC Med Genet. 2004 Mar 6;5:5. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 05, 2021 | Observed with a pathogenic variant in additional unrelated patients in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Green et al., 1999; Roux et al., 2004; Angeli et al., 2008); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 183 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 17666888, 26553399, 18758381, 10376574, 31589614, 15070423, 26346709, 17041943, 34440441) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | This sequence change creates a premature translational stop signal (p.Trp44*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 183 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs104894407, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with non-syndromic deafness (PMID: 10376574, 15070423, 26346709, 26553399). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 158605). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Leu56Argfs*26) have been determined to be pathogenic (PMID: 15967879, 16380907, 21465647, 22695344, 24158611). 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 | Eurofins Ntd Llc (ga) | Dec 16, 2016 | - - |
Hearing impairment Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at