Variant 13-20188948-AAC-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_004004.6(GJB2):c.632_633del(p.Cys211LeufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,562 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

GJB2
NM_004004.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.988

Variant links:

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]

GJB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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 0.072 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PP5

Variant 13-20188948-AAC-A is Pathogenic according to our data. Variant chr13-20188948-AAC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 158608.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 linkuse as main transcript	c.632_633del	p.Cys211LeufsTer5	frameshift_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 linkuse as main transcript	c.632_633del	p.Cys211LeufsTer5	frameshift_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.632_633del	p.Cys211LeufsTer5	frameshift_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.632_633del	p.Cys211LeufsTer5	frameshift_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250240

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135508

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461562

Hom.:

AF XY:

0.00000688

AC XY:

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2024	Observed with a pathogenic variant on the opposite allele (in trans) or phase unknown in multiple patients with sensorineural hearing loss referred for genetic testing at GeneDx and in published literature (PMID: 9529365, 12910486); Frameshift variant predicted to result in protein truncation, as the last 16 amino acids are replaced with 4 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Published functional studies demonstrate this variant impairs gap junction functions (PMID: 20863150); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17666888, 10049954, 12910486, 9529365, 20863150) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 05, 2023	This sequence change creates a premature translational stop signal (p.Cys211Leufs*5) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs587783646, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with autosomal recessive deafness (PMID: 9529365, 12910486). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 631‚Äì632del. ClinVar contains an entry for this variant (Variation ID: 158608). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects GJB2 function (PMID: 20863150). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Dec 17, 2014	- -

Hearing impairment

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

GJB2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 04, 2023

The GJB2 c.632_633delGT variant is predicted to result in a frameshift and premature protein termination (p.Cys211Leufs*5). This variant was reported as pathogenic for autosomal recessive hearing loss (Kelley. 1998. PubMed ID: 9529365; Xiao. 2010. PubMed ID: 20863150). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763087-AAC-A). Frameshift variants in GJB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over