13-20189547-C-T

Position:

chr13-20189547-C-T

Variant summary

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

The NM_004004.6(GJB2):c.35G>A(p.Gly12Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000022 in 1,591,136 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 1 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U: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 8 ACMG points.

PM1

In a helix (size 9) in uniprot entity CXB2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_004004.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-20189547-C-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.35G>A	p.Gly12Asp	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 linkuse as main transcript	c.35G>A	p.Gly12Asp	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.35G>A	p.Gly12Asp	missense_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.35G>A	p.Gly12Asp	missense_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000662

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:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000722

AC:

AN:

249434

Hom.:

AF XY:

0.0000593

AC XY:

AN XY:

135006

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000289

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:

0.0000626

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000229

AC:

AN:

1440900

Hom.:

Cov.:

AF XY:

0.0000251

AC XY:

AN XY:

717000

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000248

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:

0.0000183

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150236

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73440

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000662

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000150

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000571

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000125

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 08, 2021

Variant summary: GJB2 c.35G>A (p.Gly12Asp) results in a non-conservative amino acid change located in the Connexin, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 249434 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (7.2e-05 vs 0.00034), allowing no conclusion about variant significance. c.35G>A has been reported in the literature in individuals affected with Hearing Loss in heterozygous state (Ferraris_2002, Mahdieh_2011, Bazazzadegan_2012, Loeza-Becerra_2014, Hernandez-Juarez_2014, Gruber_2016). These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Autosomal recessive nonsyndromic hearing loss 1A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Apr 04, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 27, 2022

Reported in multiple individuals with hearing loss in published literature; however, some individuals were reported to harbor this variant as a single heterozygous variant despite family history suggestive of recessive inheritance, and others did not provide zygosity or the presence of a second variant (Ferraris et al., 2002; Mahdieh et al., 2011; Bazazzadegan et al., 2012; Loeza-Becerra et al., 2014; Hernandez-Juarez et al., 2014; Zeinali et al., 2015); 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: 12325027, 25388846, 25288386, 22695344, 24774219, 25012701, 26252218, 21388256, 31215297, 34276761, 35457072) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;D;D

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

.;.;T

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.3

D;D;.

REVEL

Pathogenic

0.88

Sift

Benign

0.030

D;D;.

Sift4G

Benign

0.17

T;T;.

Polyphen

1.0

D;D;D

Vest4

0.95

MutPred

0.93

Loss of methylation at K15 (P = 0.0616);Loss of methylation at K15 (P = 0.0616);Loss of methylation at K15 (P = 0.0616);

MVP

0.98

MPC

0.30

ClinPred

0.67

GERP RS

5.4

Varity_R

0.87

gMVP

0.96

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