13-20222791-AT-ATT
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 6P and 5B. PVS1_StrongPM2BP6BS1
The NM_001110219.3(GJB6):c.689dupA(p.Asn230LysfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00062 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00065 ( 0 hom. )
Consequence
GJB6
NM_001110219.3 frameshift
NM_001110219.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.50
Genes affected
GJB6 (HGNC:4288): (gap junction protein beta 6) Gap junctions allow the transport of ions and metabolites between the cytoplasm of adjacent cells. They are formed by two hemichannels, made up of six connexin proteins assembled in groups. Each connexin protein has four transmembrane segments, two extracellular loops, a cytoplasmic loop formed between the two inner transmembrane segments, and the N- and C-terminus both being in the cytoplasm. The specificity of the gap junction is determined by which connexin proteins comprise the hemichannel. In the past, connexin protein names were based on their molecular weight, however the new nomenclature uses sequential numbers based on which form (alpha or beta) of the gap junction is present. This gene encodes one of the connexin proteins. Mutations in this gene have been found in some forms of deafness and in some families with hidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 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. Fraction of 0.123 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 13-20222791-A-AT is Benign according to our data. Variant chr13-20222791-A-AT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95435.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000342 (52/152098) while in subpopulation AMR AF= 0.000589 (9/15270). AF 95% confidence interval is 0.000418. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GJB6 | NM_001110219.3 | c.689dupA | p.Asn230LysfsTer11 | frameshift_variant | Exon 5 of 5 | ENST00000647029.1 | NP_001103689.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.000342 AC: 52AN: 152098Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000302 AC: 76AN: 251346Hom.: 0 AF XY: 0.000302 AC XY: 41AN XY: 135834
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GnomAD4 exome AF: 0.000649 AC: 948AN: 1461700Hom.: 0 Cov.: 31 AF XY: 0.000597 AC XY: 434AN XY: 727132
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GnomAD4 genome 0.000342 AC: 52AN: 152098Hom.: 0 Cov.: 32 AF XY: 0.000310 AC XY: 23AN XY: 74292
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 04, 2022 | Observed with no other GJB6 variant in a patient with presumed autosomal recessive hearing loss, and in a patient with hearing loss attributed to neonatal meningitis in published literature (Beck et al., 2015); Frameshift variant predicted to result in protein truncation as the last 32 amino acids are lost and replaced with 10 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 25621899, 34426522, 25214170) - |
| Pathogenic, no assertion criteria provided | clinical testing | Eurofins Ntd Llc (ga) | May 20, 2013 | Frameshift mutation is of a type predicted to cause disease. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 06, 2014 | The Asn230fs variant in GJB6 has been identified in at least two other individua ls, one without clinical information and one with hearing loss (ClinVar and LMM unpublished data, respectively). In addition, this variant has been identified i n 0.1% (8/8254) of European American chromosomes by the NHLBI Exome sequencing p roject (http://evs.gs.washington.edu/EVS/). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathog enic role. This variant is predicted to cause a frameshift, which alters the pro tein?s amino acid sequence beginning at position 230 and leads to a premature te rmination codon 11 amino acids downstream. This alteration may lead to a truncat ed and altered protein. However, the role of GJB6 variants in nonsyndromic heari ng loss is currently unknown. In summary, additional information is needed to de termine the clinical significance of this variant. - |
Hidrotic ectodermal dysplasia syndrome;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B;C2675237:Autosomal dominant nonsyndromic hearing loss 3B Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 01, 2024 | This sequence change creates a premature translational stop signal (p.Asn230Lysfs*11) in the GJB6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the GJB6 protein. This variant is present in population databases (rs398124237, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with deafness (PMID: 25214170). This variant is also known as c.682insA, c.682- 683insA. ClinVar contains an entry for this variant (Variation ID: 95435). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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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