13-20222791-AT-ATT
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
Consequence
NM_001110219.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
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 AF: 0.000342 AC: 52AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000302 AC: 76AN: 251346Hom.: 0 AF XY: 0.000302 AC XY: 41AN XY: 135834
GnomAD4 exome AF: 0.000649 AC: 948AN: 1461700Hom.: 0 Cov.: 31 AF XY: 0.000597 AC XY: 434AN XY: 727132
GnomAD4 genome AF: 0.000342 AC: 52AN: 152098Hom.: 0 Cov.: 32 AF XY: 0.000310 AC XY: 23AN XY: 74292
ClinVar
Submissions by phenotype
not provided Pathogenic:1Benign:1
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) -
Frameshift mutation is of a type predicted to cause disease. -
not specified Uncertain:1
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in at least two other individua ls, one without clinical information and one with hearing loss (ClinVar and LMM unpublished data, respectively).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
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at