NM_004004.6:c.79G>A
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1
The NM_004004.6(GJB2):c.79G>A(p.Val27Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0184 in 1,614,144 control chromosomes in the GnomAD database, including 4,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_004004.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0259 AC: 3943AN: 152180Hom.: 419 Cov.: 32
GnomAD3 exomes AF: 0.0540 AC: 13514AN: 250230Hom.: 1750 AF XY: 0.0444 AC XY: 6013AN XY: 135380
GnomAD4 exome AF: 0.0176 AC: 25688AN: 1461846Hom.: 3603 Cov.: 33 AF XY: 0.0164 AC XY: 11950AN XY: 727222
GnomAD4 genome AF: 0.0259 AC: 3949AN: 152298Hom.: 418 Cov.: 32 AF XY: 0.0308 AC XY: 2293AN XY: 74480
ClinVar
Submissions by phenotype
not specified Benign:8
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Val27Ile in exon 2 of GJB2: This variant is benign based on its high frequency i n the general population (rs2274084) with a homozygous frequency of 12-20% in th e Asian population. -
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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. -
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Autosomal recessive nonsyndromic hearing loss 1A Benign:5
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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. -
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not provided Benign:4
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Autosomal dominant nonsyndromic hearing loss 3A Benign:2
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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. -
Ichthyosis, hystrix-like, with hearing loss Benign:1
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
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of c.79G>A variant (p.Val27Ile) in GJB2 gene is 27,2% (5547/ 19950 East Asian alleles with 95% CI), 21,7% in Latino population and 4,97% in all ethnic groups from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering very strong evidence against pathogenicity for autosomal recessive hearing loss variants (BA1). The c.79G>A variant has been detected in high frequency in control individuals among different population (PMID: 10633133, 10983956, 15504600, 23503914, 24645897). This variant has been found in cis with pathogenic variants, applying to BP2 (PMID: 24158611). Besides, functional studies showed that p.Val27Ile mutant generated electrical conductance equal to wild type between paired Xenopus laevis oocytes. The same result was obtained when p.Val27Ile mutant was co-injected to hWtCX30, (PMID: 16300957; BS3_Supporting). In summary, this variant meets criteria to be classified as benign for autosomal recessive non-syndromic hearing loss BA1, BP2 and BS3_Supporting. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at