rs1555341960

Positions:

• chr13-20189349-G-GC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000382848.5(GJB2):​c.232_233insG​(p.Ala78GlyfsTer24) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 ENST00000382848.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.31

Genes affected

GJB2 (HGNC:4284): (gap junction protein beta 2) This gene encodes a member of the gap junction protein family. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. 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 are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 149 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-20189349-G-GC is Pathogenic according to our data. Variant chr13-20189349-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.232_233insG	p.Ala78GlyfsTer24	frameshift_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.232_233insG	p.Ala78GlyfsTer24	frameshift_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.232_233insG	p.Ala78GlyfsTer24	frameshift_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2	c.232_233insG	p.Ala78GlyfsTer24	frameshift_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 10, 2022	This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Cys211Leufs*5) have been determined to be pathogenic (PMID: 9529365, 12910486, 20863150). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 553568). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive deafness (PMID: 17666888, 31370293, 33096615). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala78Glyfs*24) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 149 amino acid(s) of the GJB2 protein. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2023	Frameshift variant predicted to result in protein truncation, as the last 149 amino acids are replaced with 23 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 17666888, 31370293, 33096615, 24158611) -

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Aug 30, 2017

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

INGEBI, INGEBI / CONICET

Aug 21, 2020

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The c.232dupG (p.Ala78Glyfs*24) variant in the GJB2 is absent from population databases (gnomAD, GO-ESP, 1000 genomes) which meets the PM2 criteria. The c.232dupG variant is predicted to cause a premature stop codon in the only exon of GJB2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant has been detected in trans with a pathogenic variant (p.Arg143Trp) in one hearing impaired individual applying to PM3 rule (PMID: 24158611). This variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss: PM2, PVS1, PM3. -

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: rs1555341960; hg19: chr13-20763488;