rs397517206
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_001110219.3(GJB6):c.60_61delCGinsT(p.Gly21ArgfsTer13) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001110219.3 frameshift, missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB6 | NM_001110219.3 | c.60_61delCGinsT | p.Gly21ArgfsTer13 | frameshift_variant, missense_variant | Exon 5 of 5 | ENST00000647029.1 | NP_001103689.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
The Lys22ArgfsX13 variant in GJB6 has not been reported in the literature but wa s submitted to ClinVar by GeneDx (ClinVar Variation ID: 45506). This variant may be represented in the Genome Aggregation Database as two variants (a frameshift and a single nucleotide variant) which have been reported in that database at i dentical frequencies and are likely in cis, with the highest frequency of 0.04% (56/126616) in European chromosomes (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs199552278 and rs778513540). This variant is predicted to cause a frameshi ft, which alters the protein's amino acid sequence beginning at codon 22 and lea ds to a premature stop codon 13 codons downstream. This alteration is then predi cted to lead to a truncated or absent protein. However, the role of GJB6 loss of function (LOF) variants in nonsyndromic hearing loss or any phenotype is curren tly unknown. Certain missense variants in GJB6 have previously been associated w ith autosomal dominant hidrotic ectodermal dysplasia (Clouston syndrome) (Lamart ine 2000). However, the only recessive GJB6 variants with sufficient evidence fo r pathogenicity are large deletions that likely delete regulatory elements contr olling GJB2 expression. This is consistent with other overlapping pathogenic del etions that do not impact GJB6 coding sequencing. In summary, it's unknown what phenotype, if any, might be associated with either heterozygous or biallelic los s of function sequence variants in GJB6 and as such, this variant is classified as uncertain significance. ACMG/AMP Criteria applied: None. -
not provided Uncertain:1
Frameshift variant predicted to result in protein truncation as the last 240 amino acids are replaced with 12 different amino acids; Has not been previously published as pathogenic or benign to our knowledge -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at