rs1555937150
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000166.6(GJB1):c.343dup(p.Leu115ProfsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 22)
Consequence
GJB1
NM_000166.6 frameshift
NM_000166.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.399
Genes affected
GJB1 (HGNC:4283): (gap junction protein beta 1) This gene encodes a member of the gap junction protein family. The gap junction proteins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells. 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 cause X-linked Charcot-Marie-Tooth disease, an inherited peripheral neuropathy. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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. There are 95 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-71224045-A-AC is Pathogenic according to our data. Variant chrX-71224045-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 406225.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.343dup | p.Leu115ProfsTer32 | frameshift_variant | 2/2 | ENST00000361726.7 | |
GJB1 | NM_001097642.3 | c.343dup | p.Leu115ProfsTer32 | frameshift_variant | 2/2 | ||
GJB1 | XM_011530907.3 | c.343dup | p.Leu115ProfsTer32 | frameshift_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.343dup | p.Leu115ProfsTer32 | frameshift_variant | 2/2 | 1 | NM_000166.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 30, 2016 | This variant disrupts the final 169 amino acids, or about 60%, of the GJB1 protein. In addition, a different truncation downstream of this variant (p.Arg220*) has been determined to be pathogenic (PMID: 8162049, 9364054). This suggests that deletion of this region of the GJB1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with a GJB1-related disease. This sequence change inserts 1 nucleotide in exon 2 of the GJB1 mRNA (c.343dupC), causing a frameshift at codon 115. This creates a premature translational stop signal in the last exon of the GJB1 mRNA (p.Leu115Profs*32). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 169 amino acids of the GJB1 protein. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at