rs370696868

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The NM_004004.6(GJB2):c.187G>T(p.Val63Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,378 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 7.85

Variant links:

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]

GJB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 13-20189395-C-A is Pathogenic according to our data. Variant chr13-20189395-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447443.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.187G>T	p.Val63Leu	missense_variant	2/2	ENST00000382848.5	NP_003995.2	P29033H9U1J4
GJB2	XM_011535049.3 linkuse as main transcript	c.187G>T	p.Val63Leu	missense_variant	2/2		XP_011533351.1	P29033H9U1J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.187G>T	p.Val63Leu	missense_variant	2/2	1	NM_004004.6	ENSP00000372299.4		P29033
GJB2	ENST00000382844.2 linkuse as main transcript	c.187G>T	p.Val63Leu	missense_variant	1/1	6		ENSP00000372295.1		P29033

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152198

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:

0.000385

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:

0.0000239

AC:

AN:

251252

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1461062

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726662

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000445

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 19, 2023	The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant is statistically significantly enriched in affected patients as compared to ethnically matched controls. Computational tools predict that this variant is damaging. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 2023	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 63 of the GJB2 protein (p.Val63Leu). This variant is present in population databases (rs370696868, gnomAD 0.02%). This missense change has been observed in individual(s) with GJB2-related conditions (PMID: 12792423, 25266519, 34403091; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 447443). 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%. This variant disrupts the p.Val63 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 1A

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Autosomal dominant nonsyndromic hearing loss 3A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

May 08, 2023

The inherited heterozygous c.187G>T p.(Val63Leu) variant identified in the GJB2 gene has previously been reported as heterozygous in multiple individuals with non‐syndromic hearing loss [PMID: 21557232, 26252218, 26043044, 19366456, 24612839, 25266519, others] and as compound heterozygous in at least two families with recessively inherited hearing loss [PMID: 19707039, 24507663]. This variant has been deposited in ClinVar [ClinVar ID:447443] as Variant of Uncertain Significance (2 submissions) and Likely Pathogenic (1 submission), and was classified as a Variant of Uncertain by a recent study[PMID: 36048236]. In population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), the c.187G>T variant is observed at ~0.0027% minor allele frequency across populations (with 0 homozygotes), including ~0.03% minor allele frequency in East Asian sub-population which is higher than the expected maximum allele frequency for a pathogenic variant in the GJB2-related dominant hearing loss [https://cspec.genome.network/cspec/ui/svi/doc/GN005]. The c.187G>T variant in GJB2is located in exon 2 of this 2-exon gene and is predicted to replace an evolutionarily conserved valine amino acid with leucine at position 63 of the encoded protein.In silico predictions are in favor of damaging effect for p.(Val63Leu) [REVEL = 0.929]; however, there are no functional studies to support or refute these predictions. Due to the lack of compelling evidence for its pathogenicity, this inherited heterozygous c.187G>T p.(Val63Leu) variant identified in GJB2 is classified as a Variant of Uncertain Significance for GJB2-related autosomal dominant hearing loss. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.54

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

.;.;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;M;M

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.0

D;D;.

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.025

D;D;.

Polyphen

1.0

D;D;D

Vest4

0.88

MutPred

0.93

Gain of catalytic residue at V63 (P = 0.0426);Gain of catalytic residue at V63 (P = 0.0426);Gain of catalytic residue at V63 (P = 0.0426);

MVP

0.97

MPC

0.28

ClinPred

0.99

GERP RS

5.3

Varity_R

0.92

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

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