rs148136545
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_004004.6(GJB2):c.-6T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000605 in 1,613,760 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0032 ( 7 hom., cov: 33)
Exomes 𝑓: 0.00034 ( 1 hom. )
Consequence
GJB2
NM_004004.6 5_prime_UTR
NM_004004.6 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.06
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 -9 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
?
Variant 13-20189587-A-T is Benign according to our data. Variant chr13-20189587-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44721.We mark this variant Likely_benign, oryginal submissions are: {Benign=9, Uncertain_significance=1}. Variant chr13-20189587-A-T is described in Lovd as [Benign].
BS2
?
High Homozygotes in GnomAd at 7 AD,AR,Digenic gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.-6T>A | 5_prime_UTR_variant | 2/2 | ENST00000382848.5 | ||
GJB2 | XM_011535049.3 | c.-6T>A | 5_prime_UTR_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.-6T>A | 5_prime_UTR_variant | 2/2 | 1 | NM_004004.6 | P1 | ||
GJB2 | ENST00000382844.2 | c.-6T>A | 5_prime_UTR_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00318 AC: 484AN: 152070Hom.: 7 Cov.: 33
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GnomAD3 exomes AF: 0.000859 AC: 214AN: 249098Hom.: 1 AF XY: 0.000652 AC XY: 88AN XY: 134940
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GnomAD4 exome AF: 0.000335 AC: 490AN: 1461572Hom.: 1 Cov.: 32 AF XY: 0.000285 AC XY: 207AN XY: 727110
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GnomAD4 genome ? AF: 0.00319 AC: 486AN: 152188Hom.: 7 Cov.: 33 AF XY: 0.00314 AC XY: 234AN XY: 74422
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:11
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 15, 2012 | -6T>A in Exon 02 of GJB2: This variant is not expected to have clinical signific ance because it has been identified in 1.5% (55/3738) of African American chromo somes from a broad population by the NHLBI Exome Sequencing Project (http://evs. gs.washington.edu/EVS; dbSNP rs148136545) and has been reported as benign based on an equal occurance in cases and controls (Tang 2006, Al-Qahtani, 2010, Shan 2 010). - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 08, 2019 | Variant summary: GJB2 c.-6T>A is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.0012 in 275934 control chromosomes, predominantly at a frequency of 0.012 within the African subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 36-fold of the estimated maximal expected allele frequency for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss phenotype (0.00034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant, c.-6T>A, has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss, but also in controls (Gasmelseed_2004, Tang_2006, Shan_2010, Bosch_2014) and is considered by multiple authors a non-pathogenic common variant. These report(s) do not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 31, 2016 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 30, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 11, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2020 | This variant is associated with the following publications: (PMID: 28642064, 12925341, 17666888, 24706568, 25162826, 27501294, 14722929, 17041943, 19929407, 20381175) - |
Autosomal recessive nonsyndromic hearing loss 1A Uncertain:1Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 10, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Ichthyosis, hystrix-like, with hearing loss Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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 sensorineural hearing loss Benign:1
Benign, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Mar 04, 2021 | - - |
Autosomal dominant nonsyndromic hearing loss 3A Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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. - |
GJB2-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 23, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Name
Calibrated prediction
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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