rs727504309

Positions:

chr13-20189394-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM5PP3_Strong

The NM_004004.6(GJB2):c.188T>C(p.Val63Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,308 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V63L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7

Conservation

PhyloP100: 9.26

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 8 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_004004.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-20189395-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2979737.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.188T>C	p.Val63Ala	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3 linkuse as main transcript	c.188T>C	p.Val63Ala	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.188T>C	p.Val63Ala	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.188T>C	p.Val63Ala	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.0000398

AC:

AN:

251280

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.00000890

AC:

AN:

1461092

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726682

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 63 of the GJB2 protein (p.Val63Ala). This variant is present in population databases (rs727504309, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 17041943; 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: 177751). 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 observed in individuals with GJB2-related conditions (PMID: 14985372), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2022	Observed with a second GJB2 variant in an individual with hearing loss in published literature, however, the phase of these variants is unknown (Tang et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19366456, 17041943, 25388846, 30245029, 24774219) -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2017	Variant summary: The GJB2 c.188T>C (p.Val63Ala) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 5/121934 control chromosomes at a frequency of 0.000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). The variant has been reported in affected individuals in the literature, without evidence for causality. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as VUS. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 01, 2014	Variant classified as Uncertain Significance - Favor Pathogenic. The Val63Ala va riant in GJB2 has been previously reported in one individual with hearing loss w ho carried a second pathogenic GJB2 variant and was not identified in 588 contro l chromosomes (Tang, 2006). Computational analyses (conservation, AlignGVGD, Pol yPhen2, and SIFT) suggest that the Val63Ala variant may impact the protein, thou gh this information is not predictive enough to determine pathogenicity. In summ ary, the clinical significance of this variant cannot be determined with certain ty; however, based on its presence in an individual with hearing loss who carrie d a second GJB2 variant and the computational and conservation data suggestive o f an impact to the protein, we would lean towards a more likely pathogenic role. -

Autosomal recessive nonsyndromic hearing loss 1A

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 27, 2021	NM_004004.5(GJB2):c.188T>C(V63A) is a missense variant classified as a variant of uncertain significance in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. V63A has been observed in cases with relevant disease (PMID: 17041943, 24774219). Functional assessments of this variant are not available in the literature. V63A has been observed in population frequency databases (gnomAD: AMR 0.03%). In summary, there is insufficient evidence to classify NM_004004.5(GJB2):c.188T>C(V63A) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1844678:X-linked mixed hearing loss with perilymphatic gusher;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;D;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.86

.;.;D

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

M;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-4.0

D;D;.

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0090

D;D;.

Sift4G

Uncertain

0.055

T;T;.

Polyphen

1.0

D;D;D

Vest4

0.89

MutPred

0.88

Gain of ubiquitination at K61 (P = 0.078);Gain of ubiquitination at K61 (P = 0.078);Gain of ubiquitination at K61 (P = 0.078);

MVP

0.96

MPC

0.30

ClinPred

0.79

GERP RS

5.3

Varity_R

0.86

gMVP

0.94

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