chr13-20189413-G-A
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_004004.6(GJB2):c.169C>T(p.Gln57*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000906 in 1,612,288 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 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000097 ( 0 hom. )
Consequence
GJB2
NM_004004.6 stop_gained
NM_004004.6 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.94
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 53 pathogenic variants in the truncated region.
PP5
Variant 13-20189413-G-A is Pathogenic according to our data. Variant chr13-20189413-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 44725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189413-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152224Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251022Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135644
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GnomAD4 exome AF: 0.0000973 AC: 142AN: 1460064Hom.: 0 Cov.: 33 AF XY: 0.0000785 AC XY: 57AN XY: 725936
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GnomAD4 genome 0.0000263 AC: 4AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74376
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Integrating Genomics into Medicine, Frazer Institute, University Of Queensland | Jun 02, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 19, 2021 | Variant summary: GJB2 c.169C>T (p.Gln57X) 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 2.8e-05 in 251022 control chromosomes. c.169C>T has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (e.g. Wilcox_1999, Roux_2004, Snoeckx_2005, Marlin_2005). These data indicate that the variant is very likely to be associated with disease. Seven 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | May 09, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Oct 09, 2015 | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 26, 2023 | This sequence change creates a premature translational stop signal (p.Gln57*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 170 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs111033297, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with clinical features of GJB2-related deafness (PMID: 10353784, 21465647). ClinVar contains an entry for this variant (Variation ID: 44725). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Tyr65*) have been determined to be pathogenic (PMID: 9482292, 16380907). 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, 2024 | Nonsense variant predicted to result in protein truncation, as the last 170 amino acids are lost, 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: 26940866, 15547423, 18196482, 21298644, 25270357, 9482292, 25087612, 10353784, 21465647, 15150777, 16380907, 11439000, 15070423, 18324688, 20553101, 15365987, 17041943, 29106882, 29625052, 26689913, 31980526, 31589614, 15967879, 36048236, 36451132) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 11, 2022 | 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 affected with hearing loss, this variant has been seen with a single recessive pathogenic variant in the same gene. - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 19, 2017 | The p.Gln57Ter (rs111033297) has been observed in several cohorts of patients with sensorineural hearing loss, many carrying a second pathogenic variant in GJB2 (selected references: Wilcox 1999, Snoeckx 2005, Marlin 2005). This variant introduces a premature termination codon and is predicted to result in a truncated protein product. Consistent with a recessive carrier frequency, it is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.004% (identified in 11 out of 276,670 chromosomes). It is also listed in the ClinVar database as pathogenic (Variation ID: 44725). Thus, the p.Gln57Ter variant satisfies our criteria for classification as pathogenic. - |
Hearing loss Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Nov 12, 2009 | - - |
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 25, 2024 | - - |
GJB2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 05, 2024 | The GJB2 c.169C>T variant is predicted to result in premature protein termination (p.Gln57*). This variant has been reported in multiple individuals with autosomal recessive deafness (Wilcox. 1999. PubMed ID: 10353784; Dodson. 2011. PubMed ID: 21465647; Snoeckx. 2005. PubMed ID: 16380907; Marlin. 2005. PubMed ID: 15967879). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in GJB2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Rare genetic deafness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 25, 2007 | The Gln57X variant in GJB2 has been reported in at least 20 individuals with hea ring loss (Dodson 2011, Feldmann 2004, Marlin 2005, Roux 2004, Snoeckx 2005, Wil cox 1999). Most of these individuals were homozygous or compound heterozygous. I t has also been identified in 0.007% (9/128912) of European chromosomes by gnomA D (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 57, which is predicted to lead to a truncated or absent protein. Loss of function of the GJB2 gene is an established disease mech anism in autosomal recessive hearing loss. In summary, this variant meets criter ia to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PM2. - |
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
Pathogenic
D
Vest4
GERP RS
Splicing
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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