rs1326514987

Positions:

chr13-20189449-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The ENST00000382848.5(GJB2):c.133G>A(p.Gly45Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,988 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. G45E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GJB2
ENST00000382848.5 missense

Scores

Clinical Significance

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

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 Pathogenic. Variant got 11 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in ENST00000382848.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-20189448-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 13-20189449-C-T is Pathogenic according to our data. Variant chr13-20189449-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 556575.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.133G>A	p.Gly45Arg	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 linkuse as main transcript	c.133G>A	p.Gly45Arg	missense_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.133G>A	p.Gly45Arg	missense_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.133G>A	p.Gly45Arg	missense_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460824

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726506

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2024	Reported heterozygous in a patient with post-lingual hearing loss in the published literature (PMID: 27761313); however, additional clinical and inheritance information was not provided; Published functional studies demonstrate that the Cx26 protein with this variant is able to formgap junction channels at cell membranes, but channels showreduced IP3 permeability when co-expressed withwildtype Cx26 channels, consistent witha dominant negative effect on channel function (PMID: 27761313); Located in the highly conserved parahelix region of connexin 26; Not observed at significant frequency in large population cohorts (gnomAD); 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: 36048236, 27761313, 37106706, 37892203) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 23, 2021	This sequence change replaces glycine with arginine at codon 45 of the GJB2 protein (p.Gly45Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with deafness (PMID: 27761313). ClinVar contains an entry for this variant (Variation ID: 556575). 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. Experimental studies have shown that this missense change affects GJB2 function (PMID: 27761313). This variant disrupts the p.Gly45 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15633193, 16885744, 18024254, 24785414). 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 25, 2018

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly45Arg variant in GJB2 has been reported in 1 individual with non-syndromic hearing los s (Rodriguez-Paris 2016). In addition, in vitro fluorescence microscopy studies suggest impaired permeability of IP3 through the connexin-26 (GJB2) channel for the p.Gly45Arg variant, potentially in an autosomal dominant manner (Rodriguez-P aris 2016). This variant has also been identified in 1/8722 of African chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org) . Computational prediction tools and conservation analysis suggest that the p.Gl y45Arg variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion fo r a pathogenic role, the clinical significance of the p.Gly45Arg variant is unce rtain. ACMG/AMP Criteria applied: PM2; PP3; PS3_Supporting. -

Autosomal recessive nonsyndromic hearing loss 1A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Feb 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.53

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D;D;D

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.83

.;.;T

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.7

D;D;.

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0090

D;D;.

Sift4G

Uncertain

0.011

D;D;.

Polyphen

1.0

D;D;D

Vest4

0.94

MutPred

0.77

Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);

MVP

0.98

MPC

0.30

ClinPred

1.0

GERP RS

5.2

Varity_R

0.89

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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