rs1555341945

chr13-20189319-G-Achr13-20189319-G-Cchr13-20189319-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_004004.6(GJB2):c.263C>T(p.Ala88Val) 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. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A88E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.94

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 10 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_004004.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 13-20189319-G-A is Pathogenic according to our data. Variant chr13-20189319-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1458348.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.263C>T	p.Ala88Val	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.263C>T	p.Ala88Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.263C>T	p.Ala88Val	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.263C>T	p.Ala88Val	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 15, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJB2 function (PMID: 23447037). 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 missense change has been observed in individual(s) with autosomal dominant keratitis–ichthyosis–deafness (KID) syndrome (PMID: 20629838). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 88 of the GJB2 protein (p.Ala88Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;D;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.4	D;D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.90
MutPred		0.85		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.99
MPC		0.27
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.81
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-20763458;