rs111033293

Variant names:

• chr13-20189581-T-A
• rs111033293
• NM_004004.6:c.1A>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 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 NM_004004.6 initiator_codon
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.86
• Publications: 41 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: Likely_pathogenic. The variant received 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 rank	MANE	Protein	UniProt
GJB2	NM_004004.6	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.1A>T	p.Met1?	initiator_codon_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.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 1	6		ENSP00000372295.1
ENSG00000296095	ENST00000736390.1	n.232-4001A>T		intron_variant	Intron 1 of 3

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33468

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: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111906

Other (OTH) AF: 0.00 AC: 0 AN: 60382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

Feb 09, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Nonsyndromic genetic hearing loss Pathogenic:1

Mar 28, 2024

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		7.9
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
PromoterAI		-0.0097	Neutral
Varity_R		0.94
gMVP		0.86
Mutation Taster		=4/196	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs111033293; hg19: chr13-20763720;