rs371086981

Positions:

• chr13-20189580-A-C
• chr13-20189580-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM3 PP1_Moderate PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.2T>G (p.Met1Arg) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 44729, 550716, 2070085, 371781). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant has been reported in an individual with prelingual and profound hearing loss in a compound heterozygous manner with the pathogenic variant c.35delG, p.G12Vfs (1 PM3 point, Clinvar ID: 17004) and segregated in two affected siblings (PP1_Moderate, PMID:36472766). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting, PM3, PP1_Moderate (VCEP specifications version 2; 10.24.2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA387462304/MONDO:0019497/005

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004.6 start_lost
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 9.13

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 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.2T>G	p.Met1?	start_lost	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.2T>G	p.Met1?	start_lost	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.2T>G	p.Met1?	start_lost	2/2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.2T>G	p.Met1?	start_lost	1/1	6		ENSP00000372295.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

May 12, 2017

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Mar 28, 2024

The c.2T>G (p.Met1Arg) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 44729, 550716, 2070085, 371781). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant has been reported in an individual with prelingual and profound hearing loss in a compound heterozygous manner with the pathogenic variant c.35delG, p.G12Vfs (1 PM3 point, Clinvar ID: 17004) and segregated in two affected siblings (PP1_Moderate, PMID: 36472766). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting, PM3, PP1_Moderate (VCEP specifications version 2; 10.24.2023). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2023

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of the initiator codon alters GJB2 gene expression (PMID: 12189493). ClinVar contains an entry for this variant (Variation ID: 551915). Disruption of the initiator codon has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 9482292, 10218527, 18941476, 20146813, 29605365). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the GJB2 mRNA. The next in-frame methionine is located at codon 34. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	D;D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;.;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
PROVEAN	Pathogenic	-5.5	D;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.94
MutPred		0.99		Loss of stability (P = 0.0145);Loss of stability (P = 0.0145);Loss of stability (P = 0.0145);
MVP		0.99
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs371086981; hg19: chr13-20763719;