rs104894395

chr13-20189352-C-T

Variant summary

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

The NM_004004.6(GJB2):c.230G>A(p.Trp77Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GJB2 NM_004004.6 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.86

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 151 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-20189352-C-T is Pathogenic according to our data. Variant chr13-20189352-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.230G>A	p.Trp77Ter	stop_gained	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.230G>A	p.Trp77Ter	stop_gained	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.230G>A	p.Trp77Ter	stop_gained	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.230G>A	p.Trp77Ter	stop_gained	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251394 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:2

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Feb 11, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

This sequence change creates a premature translational stop signal (p.Trp77*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 150 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs104894395, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with autosomal recessive nonsyndromic hearing loss (PMID: 12792423, 30146550). ClinVar contains an entry for this variant (Variation ID: 189176). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Lys112Glufs*2) have been determined to be pathogenic (PMID: 9529365, 23141775). 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. -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 25, 2016

The p.Trp77X variant in GJB2 has been reported in several individuals with heari ng loss who were either homozygous or compound heterozygous for a second pathoge nic variant in GJB2 (Hwa 2003, Bazazzagedan 2012, Huang 2015). This variant has not been reported in large population studies. This nonsense variant leads to a premature termination codon at position 77, which is predicted to lead to a tru ncated or absent protein. Loss of function of the GJB2 gene is an established di sease mechanism in autosomal recessive nonsyndromic hearing loss. In addition, a nother nonsense variant at an adjacent nucleotide position (c.231G>A) resulting in the same amino acid change has also been reported in many individuals with he aring loss (Kelsell 1997, Scott 1998, Rickard 2001, Santos 2005, Mani 2008, Padm a 2009, Shafique 2014). Several individuals have been reported with the p.Trp77 X variant; however, the nucleotide change was not described (Cheng 2005, Bajaj 2 008, Bhalla 2009). In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive hearing loss based upon the predicted impa ct of the variant and multiple occurrences in the homozygous state as well as in compound heterozygosity with pathogenic GJB2 variants in individuals with heari ng loss. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	44
Dann	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A
Vest4		0.92
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs104894395; hg19: chr13-20763491;