13-20189434-C-T

Position:

• chr13-20189434-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_004004.6(GJB2):​c.148G>A​(p.Asp50Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 6.04

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 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 13-20189434-C-T is Pathogenic according to our data. Variant chr13-20189434-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189434-C-T is described in Lovd as [Pathogenic]. Variant chr13-20189434-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.148G>A	p.Asp50Asn	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.148G>A	p.Asp50Asn	missense_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.148G>A	p.Asp50Asn	missense_variant	2/2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.148G>A	p.Asp50Asn	missense_variant	1/1	6		ENSP00000372295.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2022	Published functional studies demonstrate a defect in intracellular trafficking to the cell memberane and, most importantly, aberrant function of connexin26 hemichannels (Di et al., 2005; Lopez et al., 2013; Taki et al., 2018); Located in highly conserved first extracellular domain of connexin 26, which is a known mutational hotspot for autosomal dominant, syndromic GJB2 disorders (Richard et al., 2002; UniProt Consortium, 2017; HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21410767, 18986886, 23797419, 22951689, 27141831, 17381453, 21999526, 22643125, 15769851, 18987669, 20101161, 15823911, 15633193, 25575739, 26444850, 23924173, 25388846, 17106596, 28158657, 18412859, 16172043, 16679758, 19793313, 19175781, 28428247, 23797420, 11918723, 26810281, 30150638, 12072059, 11912510, 28981923, 29023238, 30168495, 33502802, 31705875) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 50 of the GJB2 protein (p.Asp50Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant keratitis-ichthyosis-deafness syndrome (PMID: 11918723, 15633193, 20101161, 23924173, 25575739, 27141831). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 17020). 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: 18987669, 23797420). For these reasons, this variant has been classified as Pathogenic. -

Autosomal dominant keratitis-ichthyosis-hearing loss syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2009	- -
Pathogenic, no assertion criteria provided	clinical testing	Nemer Genomics and Translation Biomedicine Lab, American University of Beirut	-	- -

Ichthyosis, hystrix-like, with hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2009

- -

Hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Oct 17, 2006

- -

Sensorineural hearing loss disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Jan 06, 2020

- -

Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C1865234:Ichthyosis, hystrix-like, with hearing loss Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 15, 2022

ACMG classification criteria: PS3 supporting, PS4, PM1, PM2 moderate, PM6 -

Mutilating keratoderma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	.;.;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	M;M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.3	D;D;.
REVEL	Uncertain	0.64
Sift	Benign	0.033	D;D;.
Sift4G	Benign	0.11	T;T;.
Polyphen		0.99	D;D;D
Vest4		0.82
MutPred		0.90		Loss of stability (P = 0.184);Loss of stability (P = 0.184);Loss of stability (P = 0.184);
MVP		0.97
MPC		0.27
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.77
gMVP		0.93

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

Other links and lift over

dbSNP: rs28931594; hg19: chr13-20763573;