NM_004004.6:c.428G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_004004.6(GJB2):c.428G>A(p.Arg143Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,994 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R143L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 6.12

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 16 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

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-20189154-C-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 13-20189154-C-T is Pathogenic according to our data. Variant chr13-20189154-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17017.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.428G>A	p.Arg143Gln	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2	P29033H9U1J4
GJB2	XM_011535049.3 link	c.428G>A	p.Arg143Gln	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.428G>A	p.Arg143Gln	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4		P29033
GJB2	ENST00000382844.2 link	c.428G>A	p.Arg143Gln	missense_variant	Exon 1 of 1	6		ENSP00000372295.1		P29033

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:5

Mar 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 03, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GJB2 c.428G>A (p.Arg143Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 125474 control chromosomes. The variant has been reported in affected individuals in the heterozygous state, suggesting a dominant role of the variant. However, compound heterozygotes have been reported who have severe/profound hearing loss, indicating a more severe phenotype than individuals with only one variant. The variant was shown to co-segregate with disease in multiple families, with the exception of an affected indivdual not carrying the variant (Loffler_2001), and one unaffected family member in each study carrying the variant, suggestive of incomplete penetrance (Riahi_2013, Bonyadi_2009). One database classified this variant as pathogenic. In addition, p.Phe142Leu, p.Arg143Trp, p.Arg143Leu have been reported to associate with NSHL, suggesting Phe142-Arg143 is a mutation hot-spot. Taken together, this variant is classified as pathogenic. -

Jan 28, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 19, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.428G>A variant is classified as a PATHOGENIC variant (PS2, PS3, PS4, PP3, PP5) This variant is a single nucleotide change from a guanine to a adenine at position 428 which is predicted to change the arginine at position 143 to glutamine. The variant is in exon 2 and is located in Connexin protein domain of the GJB2 gene. The variant has been reported in the heterozygous state in multiple individuals, and in several families segregating with high frequency hearing loss, indicating a dominant effect of this mutation in hearing loss. This variant cam also results in severe hearing loss when present in the compound heterozygous state (PMID: 11313763, 23856378, 22991996). The variant is in dbSNP (rs104894401) but is absent from population databases (PS4). Functional studies have shownthat this variant can inhibit the transfer of calcein in cells stably expressing the gap junction protein connexin 26 (Cx26), demonstrating that the dominant negative effect of this variant on wild type Cx26 (PMID: 21040787) (PS3). Previous parental testing on the GJB2 gene has confirmed that this is a De novo variant in the patient (MG WCH report: #41493 & #41494, reported date: 17/04/2014) (PS2). The variant has been reported in ClinVar (Variation ID: 17017) and HGMD (Accession: CM010311) as pathogenic (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3). -

Autosomal dominant nonsyndromic hearing loss 3A

Pathogenic:3Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 28, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

May 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 143 of the GJB2 protein (p.Arg143Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness with incomplete penetrance and/or autosomal recessive deafness (PMID: 11313763, 22991996, 25752103, 31379920). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17017). 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: 20096356, 21040787). This variant disrupts the p.Arg143 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9393973, 15235031, 15365987, 15617546, 18941476, 19715472). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Dec 08, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 16, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.428 G>A (p.R143Q) variant in the GJB2 gene has been reported previously in the compound heterozygous state in multiple unrelated individuals with congenital, profound, non-syndromic, sensorineural deafness; however, c.428 G>A has also been reported in the heterozygous state in both mildly affected and unaffected relatives of these individuals, indicating that this variant may exhibit autosomal dominant inheritance with incomplete penetrance, but also result in severe hearing loss when present in trans with an autosomal recessive GJB2 variant (Loffler et al., 2001; Bonyadi et al., 2009; Huang et al., 2013; Riahi et al., 2013). The c.428 G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice models predict that c.428 G>A may create a cryptic splice acceptor site that could supplant the natural splice acceptor site for intron 1. However, in the absence of RNA/functional studies, the actual effect of the c.428 G>A change in this individual is unknown. If c.428 G>A does not alter splicing, it will result in the R143Q missense change. The R143Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and this substitution occurs at a position that is conserved across species. Functional studies of the R143Q missense variant have demonstrated that this variant can participate in forming gap junctions, but the resulting channels exhibit both impaired function and permeability (Yum et al., 2010; Zhang et al., 2011). We interpret c.428 G>A (p.R143Q) as a pathogenic variant. -

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

Mar 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;D;D

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

.;.;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

M;M;M

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.3

N;N;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.0030

D;D;.

Polyphen

1.0

D;D;D

Vest4

0.60

MutPred

0.96

Loss of MoRF binding (P = 0.0658);Loss of MoRF binding (P = 0.0658);Loss of MoRF binding (P = 0.0658);

MVP

0.98

MPC

0.29

ClinPred

0.98

GERP RS

5.5

Varity_R

0.81

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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