13-20188984-C-T

Position:

• chr13-20188984-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.598G>A​(p.Gly200Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.20

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 helix (size 31) in uniprot entity CXB2_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_004004.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 13-20188984-C-T is Pathogenic according to our data. Variant chr13-20188984-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.598G>A	p.Gly200Arg	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.598G>A	p.Gly200Arg	missense_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.598G>A	p.Gly200Arg	missense_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2	c.598G>A	p.Gly200Arg	missense_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Institut Pasteur du Maroc	Apr 01, 2016	Pathogenic -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 08, 2022	Variant summary: GJB2 c.598G>A (p.Gly200Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251254 control chromosomes. c.598G>A has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals from diverse ethnicities affected with Autosomal Recessive Non-Syndromic Hearing Loss (example, Liu_2009, Bliznets_2012, Chaleshtori_2005, Shafique_2014, Bakhchane_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating improper trafficking with intracellular aggregation (Ambrosi_2013). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 08, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 200 of the GJB2 protein (p.Gly200Arg). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJB2 function (PMID: 23967136). 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. ClinVar contains an entry for this variant (Variation ID: 225222). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 21094084, 24949729). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jan 21, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;D;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.97	.;.;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.9	M;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.6	D;D;.
REVEL	Pathogenic	0.71
Sift	Benign	0.041	D;D;.
Sift4G	Uncertain	0.037	D;D;.
Polyphen		0.99	D;D;D
Vest4		0.90
MutPred		0.82		Loss of glycosylation at S199 (P = 0.0945);Loss of glycosylation at S199 (P = 0.0945);Loss of glycosylation at S199 (P = 0.0945);
MVP		0.97
MPC		0.23
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.75
gMVP		0.91

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: rs786204597; hg19: chr13-20763123; COSMIC: COSV101241470;