rs72561725
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_004004.6(GJB2):c.-15C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,612,768 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.015 ( 57 hom., cov: 33)
Exomes 𝑓: 0.0016 ( 54 hom. )
Consequence
GJB2
NM_004004.6 5_prime_UTR
NM_004004.6 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.62
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 Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
?
Variant 13-20189596-G-A is Benign according to our data. Variant chr13-20189596-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 94388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189596-G-A is described in Lovd as [Benign].
BA1
?
GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.-15C>T | 5_prime_UTR_variant | 2/2 | ENST00000382848.5 | ||
GJB2 | XM_011535049.3 | c.-15C>T | 5_prime_UTR_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.-15C>T | 5_prime_UTR_variant | 2/2 | 1 | NM_004004.6 | P1 | ||
GJB2 | ENST00000382844.2 | c.-15C>T | 5_prime_UTR_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0147 AC: 2229AN: 152118Hom.: 57 Cov.: 33
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GnomAD3 exomes AF: 0.00383 AC: 954AN: 248940Hom.: 20 AF XY: 0.00260 AC XY: 351AN XY: 134926
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GnomAD4 exome AF: 0.00157 AC: 2300AN: 1460532Hom.: 54 Cov.: 31 AF XY: 0.00131 AC XY: 953AN XY: 726662
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GnomAD4 genome ? AF: 0.0147 AC: 2237AN: 152236Hom.: 57 Cov.: 33 AF XY: 0.0139 AC XY: 1034AN XY: 74442
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 07, 2012 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 05, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 14, 2013 | -15C>T in Exon 02 of GJB2: This variant is not expected to have clinical signifi cance because it has been identified in 5.2% (228/4406) of African American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu) - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 14, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 27, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2023 | - - |
Autosomal recessive nonsyndromic hearing loss 1A Benign:2
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Ichthyosis, hystrix-like, with hearing loss Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Nonsyndromic genetic hearing loss Benign:1
Benign, criteria provided, single submitter | clinical testing | INGEBI, INGEBI / CONICET | Aug 31, 2020 | Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.-15C>T variant in GJB2 gene is 4,86% (1271/24918 African chromosomes with 95%CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/). This is a high enough frequency, based on the thresholds defined by the ClinGen Hearing Loss Expert Panel, for autosomal recessive hearing loss variants to apply for BA1 rule. This variant is frequent (above 6%) in controls subjects from different African populations (PS4 not met, PMID: 27501294, 21392827) Benign computational verdict prediction from DANN and CADD predictors and no conservation between species (GERPscore:-5.08) applying to BP4 rule. In summary, this variant meets criteria to be classified as benign for non-syndromic hearing loss (BA1, BP4). - |
Autosomal dominant nonsyndromic hearing loss 3A Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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