rs587783646

Variant names:

• chr13-20188948-AAC-A
• rs587783646
• NM_004004.6:c.632_633delGT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_004004.6(GJB2):​c.632_633delGT​(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.988
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• Bart-Pumphrey syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• ichthyosis, hystrix-like, with hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• keratoderma hereditarium mutilans

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• palmoplantar keratoderma-deafness syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• autosomal recessive nonsyndromic hearing loss 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• autosomal dominant keratitis-ichthyosis-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
• autosomal dominant nonsyndromic hearing loss 3A

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• KID syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296095 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 7 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 158608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6	c.632_633delGT	p.Cys211LeufsTer5	frameshift_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.632_633delGT	p.Cys211LeufsTer5	frameshift_variant	Exon 2 of 2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.632_633delGT	p.Cys211LeufsTer5	frameshift_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.632_633delGT	p.Cys211LeufsTer5	frameshift_variant	Exon 1 of 1	6		ENSP00000372295.1
ENSG00000296095	ENST00000736390.1	n.232-3370_232-3369delGT		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250240 AF XY: 0.00000738

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461562 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 727076

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:3

Dec 17, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 26, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID:17935238). (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 2 of 2). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (P) 0600 - Variant is located in an annotated domain or motif. A small region of the connexin domain (PDB) is predicted to be lost. (N) 0705 - No comparable variants have previous evidence for pathogenicity. One protein truncating variant downstream has been reported as a variant of uncertain significance (ClinVar). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple unrelated patients with autosomal recessive non-syndromic hearing loss (PMIDs: 9529365, 17666888 and 28405014), and as pathogenic in ClinVar and the Deafness Variation Database. (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional study showed the mutant protein had impaired cellular localisation (PMID:20863150). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:3

Mar 29, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Dec 06, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 631–632del. 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. -

Hearing impairment Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GJB2-related disorder Pathogenic:1

Oct 04, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.99
Mutation Taster		=4/196	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587783646; hg19: chr13-20763087;