rs1555937084

chrX-71223889-A-AC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000166.6(GJB1):c.183dup(p.Ser62GlnfsTer5) 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 (★). Synonymous variant affecting the same amino acid position (i.e. N61N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GJB1 NM_000166.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.639

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]

ACMG classification

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 144 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-71223889-A-AC is Pathogenic according to our data. Variant chrX-71223889-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 477590.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.183dup	p.Ser62GlnfsTer5	frameshift_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.183dup	p.Ser62GlnfsTer5	frameshift_variant	2/2
GJB1	XM_011530907.3	c.183dup	p.Ser62GlnfsTer5	frameshift_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.183dup	p.Ser62GlnfsTer5	frameshift_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 21, 2018

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. 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. This variant has not been reported in the literature in individuals with GJB1-related disease. ClinVar contains an entry for this variant (Variation ID: 477590). This sequence change results in a premature translational stop signal in the GJB1 gene (p.Ser62Glnfs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 222 amino acids (~78%) of the GJB1 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555937084; hg19: chrX-70443739;