rs111033293

Positions:

• chr13-20189581-T-A
• chr13-20189581-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The 1A>T (p.Met1Leu) 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, 2070085, 551915, 371781). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting (VCEP specifications version 2; 10.18.2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA387462311/MONDO:0019497/005

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GJB2 ENST00000382848.5 start_lost
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• 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 Likely_pathogenic. Variant got 9 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.1A>T	p.Met1?	start_lost	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.1A>T	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.1A>T	p.Met1?	start_lost	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2	c.1A>T	p.Met1?	start_lost	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461700 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727156

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely 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

Feb 09, 2017

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Mar 28, 2024

The 1A>T (p.Met1Leu) 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, 2070085, 551915, 371781). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting (VCEP specifications version 2; 10.18.2023). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 03, 2023

This sequence change affects the initiator methionine of the GJB2 mRNA. The next in-frame methionine is located at codon 34. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 9482292, 10218527, 18941476, 20146813, 29542069, 29605365). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550716). Studies have shown that disruption of the initiator codon alters GJB2 gene expression (PMID: 12189493). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Uncertain	0.79	D;D;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;.;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-2.8	D;D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0070	D;D;.
Polyphen		0.93	P;P;P
Vest4		0.91
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.0023);Gain of catalytic residue at M1 (P = 0.0023);Gain of catalytic residue at M1 (P = 0.0023);
MVP		0.98
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.94
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs111033293; hg19: chr13-20763720;