13-20189386-C-A

Position:

• chr13-20189386-C-A

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.196G>T​(p.Asp66Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.86

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, 0.995
• PP5: Variant 13-20189386-C-A is Pathogenic according to our data. Variant chr13-20189386-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 586962.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.196G>T	p.Asp66Tyr	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.196G>T	p.Asp66Tyr	missense_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.196G>T	p.Asp66Tyr	missense_variant	2/2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.196G>T	p.Asp66Tyr	missense_variant	1/1	6		ENSP00000372295.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sensorineural hearing loss disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratoire de Genetique Biologique, CHU de Poitiers

Oct 03, 2018

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 66 of the GJB2 protein (p.Asp66Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (Invitae). ClinVar contains an entry for this variant (Variation ID: 586962). 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. This variant disrupts the p.Asp66 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21055240, 24737404). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;.;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	1.0	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H;H;H
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-9.0	D;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.97
MutPred		0.93		Gain of catalytic residue at P70 (P = 0.0651);Gain of catalytic residue at P70 (P = 0.0651);Gain of catalytic residue at P70 (P = 0.0651);
MVP		0.97
MPC		0.30
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.98

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: rs104894403; hg19: chr13-20763525;