rs72561723

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_004004.6(GJB2):c.134G>A(p.Gly45Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,102 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: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.85

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a chain Gap junction beta-2 protein (size 225) in uniprot entity CXB2_HUMAN there are 70 pathogenic changes around while only 16 benign (81%) in NM_004004.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 13-20189448-C-T is Pathogenic according to our data. Variant chr13-20189448-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17033.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 link	c.134G>A	p.Gly45Glu	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2	P29033H9U1J4
GJB2	XM_011535049.3 link	c.134G>A	p.Gly45Glu	missense_variant	Exon 2 of 2		XP_011533351.1	P29033H9U1J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5 link	c.134G>A	p.Gly45Glu	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4		P29033
GJB2	ENST00000382844.2 link	c.134G>A	p.Gly45Glu	missense_variant	Exon 1 of 1	6		ENSP00000372295.1		P29033

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250912

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000212

AC:

AN:

1460784

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726468

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000756

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

AF:

0.0000263

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:2

Aug 21, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GJB2 c.134G>A (p.Gly45Glu) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092)/first extracellular loop domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250912 control chromosomes. c.134G>A has been reported as a de-novo variant or as a somatic mosaic in the literature in multiple individuals affected with Keratitis Ichthyosis Deafness Syndrome (KID) (Janecke_2005, Griffith_2006, Jonard_2008, Sbidian_2010, Ogawa_2014, Eskin-Schwartz_2016). These data indicate that the variant is very likely to be associated with disease. Co-occurrence in cis with another pathogenic variant have been reported in the Japanese population (GJB2 c.408C>A, p.Tyr436*), providing supporting evidence for a benign role in the setting of Autosomal Recessive Non-syndromic deafness (Fuse_1999, Ogawa_2014). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a complete inability to form functional gap junctions (Rodriguez-Paris_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant when observed in isolation was classified as pathogenic for a phenotype of KID. -

Dec 13, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Autosomal dominant keratitis-ichthyosis-hearing loss syndrome

Pathogenic:2

Dec 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 21, 2023

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_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with bi-allelic loss-of-function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0254 - This variant is confirmed mosaic. (I) 0304 - Variant is present in gnomAD v3 <0.01 (4 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated connexin domain (DECIPHER). (I) 0801 - This variant has been inherited as well as detected germline mosaic in individuals with autosomal dominant keratitis-ichthyosis-deafness syndrome in the absence of p.(Tyr136*). This variant and nonsense variant p.(Tyr136*) in cis are reported to be associated with autosomal recessive deafness. Additionally this variant has been identified somatic mosaic in individuals with porokeratotic eccrine ostial and dermal duct nevus (PEODDN) and nevoid spiny hyperkeratosis (ClinVar, Deafness Variation db, PMID:25692760, PMID:32120898, PMID:27087580, PMID:24785414, PMID:20412116). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutagenesis studies showed cells co-transfected with this variant and wild type, failed to form gap junctions, demonstrated aberrant gating activity, and resulted in cell death (PMID:27761313, PMID:24785414). Additionally, mutagenesis studies showed this variant, when in cis with the nonsense p.(Tyr136*) variant, frequently seen in the Japanese population, cancels the dominant lethal effects of p.(Gly45Glu), causing autosomal recessive non-syndromic deafness (PMID:32120898, PMID 24785414, PMID: 27761313). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:2

Mar 04, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a dominant negative effect on hemichannel function, resulting in increased cell death (PMID: 17428836, 22031297); Published functional studies demonstrate that the dominant negative effect of p.(G45E) on gap junction formation is neutralized by the presence of p.(Y136*) on the same allele (in cis), and that the complex allele results instead in a loss of protein function (PMID: 27761313); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24359977, 27087580, 33780732, 16950989, 21292415, 20584891, 30287322, 12560944, 23756814, 19043807, 26763877, 25388846, 31160754, 10633133, 31331740, 17146396, 17428836, 22031297, 10501520, 15633193, 38069086, 36048236, 24785414, 16885744, 18024254, 20412116, 36736132, 34916582, 27761313) -

Jun 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 45 of the GJB2 protein (p.Gly45Glu). This variant is present in population databases (rs72561723, gnomAD 0.003%). This variant has been observed in individual(s) with autosomal dominant keratitis-ichthyosis-deafness syndrome, in the absence of p.Tyr136* (PMID: 15633193, 16885744, 18024254, 24785414). In at least one individual the variant was observed to be de novo. Therefore, when present alone (i.e. without a loss of function variant in cis that causes nonsense-mediated decay of the transcript), this variant is expected to be causative for autosomal dominant keratitis-ichthyosis-deafness syndrome. This variant has also been reported in combination with p.Tyr136* in individuals with autosomal recessive non-syndromic deafness (PMID: 10501520, 26763877); the p.[Tyr136*;Gly45Gly] haplotype is expected to be causative for autosomal recessive non-syndromic deafness. ClinVar contains an entry for this variant (Variation ID: 17033). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 17428836, 22031297, 24785414, 27761313). For these reasons, this variant has been classified as Pathogenic. -

Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A

Pathogenic:1

Apr 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;D;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

.;.;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

M;M;M

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.2

D;D;.

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0030

D;D;.

Sift4G

Uncertain

0.022

D;D;.

Polyphen

1.0

D;D;D

Vest4

0.97

MutPred

0.90

Gain of solvent accessibility (P = 0.0281);Gain of solvent accessibility (P = 0.0281);Gain of solvent accessibility (P = 0.0281);

MVP

0.99

MPC

0.31

ClinPred

0.99

GERP RS

5.2

Varity_R

0.89

gMVP

0.97

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over