chr13-20189107-C-T

Position:

chr13-20189107-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_004004.6(GJB2):c.475G>A(p.Asp159Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: -0.0480

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 Uncertain_significance. Variant got 0 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

BP4

Computational evidence support a benign effect (MetaRNN=0.20563743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 link	c.475G>A	p.Asp159Asn	missense_variant	2/2	ENST00000382848.5	NP_003995.2	P29033H9U1J4
GJB2	XM_011535049.3 link	c.475G>A	p.Asp159Asn	missense_variant	2/2		XP_011533351.1	P29033H9U1J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5 link	c.475G>A	p.Asp159Asn	missense_variant	2/2	1	NM_004004.6	ENSP00000372299.4		P29033
GJB2	ENST00000382844.2 link	c.475G>A	p.Asp159Asn	missense_variant	1/1	6		ENSP00000372295.1		P29033

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000836

AC:

AN:

251088

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

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:

0.000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

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:

0.0000375

Gnomad4 NFE exome

AF:

0.0000576

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000818

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 09, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 09, 2021	NM_004004.5(GJB2):c.475G>A(D159N) is a missense variant classified as a variant of uncertain significance in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. D159N has been observed in cases with relevant disease (PMID: 19366456, 17666888, 14985372). Functional assessments of this variant are available in the literature (PMID: 17077310). D159N has been observed in population frequency databases (gnomAD: NFE 0.02%). In summary, there is insufficient evidence to classify NM_004004.5(GJB2):c.475G>A(D159N) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 02, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 159 of the GJB2 protein (p.Asp159Asn). This variant is present in population databases (rs373684994, gnomAD 0.02%). This missense change has been observed in individual(s) with deafness (PMID: 16380907, 17666888, 25493717). ClinVar contains an entry for this variant (Variation ID: 438618). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Asp159 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been observed in individuals with GJB2-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2020	Observed in patients with hearing loss in published literature; limited information is available for these patients, and the variant was observed with no other GJB2 variant in at least one case (Cryns et al., 2004; Snoeckx et al., 2005; Dai et al., 2009; Qing et al., 2015); In vitro functional studies suggest the variant does not affect voltage-activation of hemichannels; however, data was not available for review (Daniel et al., 2006); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 19366456, 25493717, 16380907, 14985372, 25388846, 17077310, 17666888, 17041943) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 28, 2022

Variant summary: GJB2 c.475G>A (p.Asp159Asn) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251088 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (8.4e-05 vs 0.00034), allowing no conclusion about variant significance. c.475G>A has been reported in the literature in cohorts with hearing loss (example, Cryns_2004, Snoeckx_2005, Putcha_2007, Dai_2009, Qing_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Uncertain

0.62

D;D;D

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.70

.;.;T

M_CAP

Benign

0.043

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.31

MutationAssessor

Benign

0.57

N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.2

N;N;.

REVEL

Benign

0.25

Sift

Benign

0.74

T;T;.

Sift4G

Benign

0.64

T;T;.

Polyphen

0.0

B;B;B

Vest4

0.061

MVP

0.81

MPC

0.038

ClinPred

0.026

GERP RS

3.1

Varity_R

0.063

gMVP

0.74

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