13-20223450-C-T

Position:

chr13-20223450-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001110219.3(GJB6):c.31G>A(p.Gly11Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,950 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GJB6
NM_001110219.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 2.96

Variant links:

Genes affected

GJB6 (HGNC:4288): (gap junction protein beta 6) Gap junctions allow the transport of ions and metabolites between the cytoplasm of adjacent cells. They are formed by two hemichannels, made up of six connexin proteins assembled in groups. Each connexin protein has four transmembrane segments, two extracellular loops, a cytoplasmic loop formed between the two inner transmembrane segments, and the N- and C-terminus both being in the cytoplasm. The specificity of the gap junction is determined by which connexin proteins comprise the hemichannel. In the past, connexin protein names were based on their molecular weight, however the new nomenclature uses sequential numbers based on which form (alpha or beta) of the gap junction is present. This gene encodes one of the connexin proteins. Mutations in this gene have been found in some forms of deafness and in some families with hidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]

GJB6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 13-20223450-C-T is Pathogenic according to our data. Variant chr13-20223450-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20223450-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB6	NM_001110219.3 link	c.31G>A	p.Gly11Arg	missense_variant	5/5	ENST00000647029.1	NP_001103689.1	O95452A0A024RDS4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB6	ENST00000647029.1 link	c.31G>A	p.Gly11Arg	missense_variant	5/5		NM_001110219.3	ENSP00000493834.1		O95452

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152118

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250650

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135560

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727222

show subpopulations

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

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hidrotic ectodermal dysplasia syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 02, 2022	ACMG classification criteria: PS1 strong, PS3 supporting, PS4 strong, PM2 supporting, PP1 strong, PP3 supporting -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 04, 2022	The GJB6 c.31G>A variant is classified as a PATHOGENIC variant (PS4, PS3_supporting, PP1_moderate, PM2, PP3) The variant is a single nucleotide change in exon 5/5 of the GJB6 gene, which is predicted to change the amino acid glycine at position 11 in the protein to arginine. This is a recurrent pathogenic variant in the GJB6 gene. This variant has been previously reported in more than 10 unrelated individuals affected with Clouston syndrome and segregated with disease in affected family members in multiple families (PMID: 11017065, 20536673) (PS4) (PP1_moderate). Functional studies have demonstrated that this variant causes gain of hemichannel function, resulting in increased cells apoptosis and altered cell proliferation (PMID: 12419304, 15213106) (PS3_supporting). This variant is in dbSNP (rs104894415) but is rare in population databases (gnomAD: 1/152118, 0 homozygote) (PM2). This variant has been reported in ClinVar (Variation ID: 5544) and HGMD (Accession no: CM002605) as pathogenic/ disease causing. Computational predictions support a deleterious effect on the gene or gene product (PP3). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Loss of function premature termination codon variants are associated with deafness 1B (MIM#612645) and autosomal recessive digenic GJB2/GJB6 deafness (MIM#220290). Dominant negative missense variants are associated with autosomal dominant deafness 3B (MIM#612643) (PMID: 10471490). Gain of function missense variants are associated with autosomal dominant ectodermal dysplasia 2 (MIM#129500) (PMID: 15213106). (I) 0108 - This gene is associated with both recessive and dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 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 strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in multiple unrelated individuals with ectodermal dysplasia (ClinVar, PMID: 36926140). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 01, 2014	The p.Gly11Arg variant in GJB6 is one of the four pathogenic variant associated with hidrotic ectodermal dysplasia 2 (Clouston syndrome, HED2) and has been repo rted in >10 individuals with HED2 and segregated with disease in >30 affected fa mily members (Chen 2010, Common 2002, Fujimoto 2013, Lamartine 2000). In additi on, this variant has not been identified in large population studies. In summary , this variant meets our criteria to be classified as pathogenic (http://www.par tners.org/personalizedmedicine/LMM). -

Hidrotic ectodermal dysplasia syndrome;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B;C2675237:Autosomal dominant nonsyndromic hearing loss 3B

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 20, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 11 of the GJB6 protein (p.Gly11Arg). This variant is present in population databases (rs104894415, gnomAD 0.0009%). This missense change has been observed in individual(s) with ectodermal dysplasia (PMID: 11017065, 12788524, 23926005, 23981984, 24514865, 26551294, 27817781). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5544). 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 not expected to disrupt GJB6 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GJB6 function (PMID: 12419304, 15213106, 15769851). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2023	One of the most common, recurrent GJB6 pathogenic variants causing hidrotic ectodermal dysplasia, located in the cytoplasmic amino-terminus of the gap junction protein connexin 30; Functional in vitro studies have shown that G11R impairs trafficking of connexin 30 to the cell membrane, and forms gap junctions in keratinocyte cultures when co-expressed with other connexins (Di et al., 2005); other studies demonstrate gain of hemichannel function with leakage of ATP into the extracellular medium, increased cell apoptosis, and altered cell proliferation (Essenfelder et al. 2004; Lu Y at al., 2018); Same amino acid substitution caused by a different nucleotide change (c.31 G>C) has been reported as pathogenic in the published literature in association with hidrotic ectodermal dysplasia (Fujimoto et al., 2013; Kutkowska-Kazmierczak et al., 2015); 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: 12419304, 23926005, 24514865, 11017065, 27817781, 12788524, 27643550, 23219093, 20536673, 30043857, 30983611, 15213106, 36147510, 33074302, 23981984, 15769851, 25575739) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	GJB6: PP1:Strong, PM2, PP4:Moderate, PS4:Moderate -

GJB6-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

This variant has been previously reported as a heterozygous change in patients with Ectodermal dysplasia 2, Clouston type (PMID: 11017065, 12419304, 12788524, 15213106, 15769851, 23926005, 23981984, 24514865, 20301379, 26551294). Functional studies have demonstrated a deleterious effect on protein function (PMID: 12419304, 15213106, 15769851). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.00039% (1/250650) and thus is presumed to be rare. The c.31G>A (p.Gly11Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.31G>A (p.Gly11Arg) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;D;D;D;D;D;D;D;D;D;D;.;.;.;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

.;.;.;.;.;.;.;.;.;.;D;D;D;D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

M;M;M;M;M;M;M;M;M;M;M;.;.;.;.

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.7

D;.;D;D;.;.;D;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0030

D;.;D;D;.;.;D;.;.;.;.;.;.;.;.

Sift4G

Uncertain

0.015

D;.;D;D;.;.;D;.;.;.;.;.;.;.;.

Polyphen

1.0

D;D;D;D;D;D;D;D;D;D;D;.;.;.;.

Vest4

0.89

MutPred

0.88

Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);

MVP

0.95

MPC

0.45

ClinPred

0.86

GERP RS

5.4

Varity_R

0.65

gMVP

0.96

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