13-20189197-C-T

Position:

chr13-20189197-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The ENST00000382848.5(GJB2):c.385G>A(p.Glu129Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E129E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

GJB2
ENST00000382848.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.24

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 1 ACMG points.

PM1

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

BP4

Computational evidence support a benign effect (MetaRNN=0.30677164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.385G>A	p.Glu129Lys	missense_variant	2/2	ENST00000382848.5	NP_003995.2	P29033H9U1J4
GJB2	XM_011535049.3 linkuse as main transcript	c.385G>A	p.Glu129Lys	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.385G>A	p.Glu129Lys	missense_variant	2/2	1	NM_004004.6	ENSP00000372299.4		P29033
GJB2	ENST00000382844.2 linkuse as main transcript	c.385G>A	p.Glu129Lys	missense_variant	1/1	6		ENSP00000372295.1		P29033

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152206

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:

0.00

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:

0.0000639

AC:

AN:

250484

Hom.:

AF XY:

0.0000738

AC XY:

AN XY:

135498

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.0000973

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000540

AC:

AN:

1461612

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000629

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000657

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	The p.Glu129Lys variant in GJB2 has been reported in 5 individuals with sensorineural hearing loss (Kenna 2001, Dalamón 2005, Najmabadi 2005, Primignani 2009, Putcha 2007). Only 1 of these individuals had a variant on the other allele, though the one other variant (Ala40Gly) is also of unknown significance. In another family, both the father and proband had unilateral high frequency sensorineural hearing loss raising the possibility of a dominant pattern of inheritance (Kenna 2001) though this is not consistent with the other 4 cases in the literature. This variant has not been identified in large and broad ethnically-matched populations by NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, additional data is needed to determine the clinical significance of this variant; however, given the absence of clear disease-causing variants on the second allele of any of the reported case, we would lean towards a more likely benign interpretation. ACMG/AMP Criteria applied: BP2. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2024	Observed multiple times in individuals with hearing loss; however, it is most commonly observed as heterozygous in cases of sporadic hearing loss where no other GJB2 variant is identified (PMID: 15666300, 17671735, 24158611); Also observed on the opposite allele (in trans) from the c.35delG pathogenic variant in an individual without hearing loss (PMID: 21916817); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22695344, 11556849, 24158611, 25447126, 25388846, 24156272, 28483220, 19887791, 19081147, 19371219, 17666888, 15964725, 17671735, 25012701, 12172394, 12925341, 21916817, 30245029, 30275481, 33096615, 27169813, 15666300) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 129 of the GJB2 protein (p.Glu129Lys). This variant is present in population databases (rs397516875, gnomAD 0.01%). This missense change has been observed in individual(s) with GJB2-related conditions (PMID: 19371219, 33096615). ClinVar contains an entry for this variant (Variation ID: 44747). 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 not expected to disrupt GJB2 protein function. 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	Eurofins Ntd Llc (ga)	Dec 12, 2017	- -

Autosomal recessive nonsyndromic hearing loss 1A

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 12, 2017	A heterozygous missense variant was identified, NM_004004.5(GJB2):c.385G>A in exon 2 of the GJB2 gene. This substitution creates a minor amino acid change from an glutamic acid to a lysine at position 129, NP_003995.2(GJB2):p.(Glu129Lys). The glutamic acid at this position has low conservation (100 vertebrates, UCSC). In silico predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). This variant has been previously observed in other deafness cases (Kenna, MA. et al. (2001), Dalamon, V. et al. (2005), Wu, B-L. et al. (2002) and Toth, T. et al. (2007)) and reported as PATHOGENIC in the Deafness Variation Database but evidence for its pathogenicity is conflicting and it is designated as a variant of uncertain significance in ClinVar. This variant is present in the gnomAD population database at a frequency of 0.0057% (14/245256, 0 hom). It is not situated in a known functional domain. The homozygous presence of the NM_004004.5(GJB2):c.101T>C variant in the same patient suggests that this variant (NM_004004.5(GJB2):c.385G>A) is in cis with one of the alleles. Based on current information, this variant has been classified as a VARIANT of UNKNOWN SIGNIFICANCE (VUS). -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 26, 2023

Variant summary: GJB2 c.385G>A (p.Glu129Lys) results in a conservative amino acid change located in the Connexin, N-terminal (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 250484 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (6.4e-05 vs 0.00034), allowing no conclusion about variant significance. c.385G>A has been reported in the literature in heterozygous individuals affected with Non-Syndromic Hearing Loss (Example: Buonfiglio_2020, Dalamn_2005, Kenna_2001, Putcha_2007, Tth_2007, Wu_2002), and also observed in an unaffected child with a pathogenic variant (Chinetti_2011). These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 33096615, 21916817, 15964725, 24158611, 11556849, 17666888, 17671735, 12172394).Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Nonsyndromic genetic hearing loss

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

INGEBI, INGEBI / CONICET

Aug 31, 2020

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of c.385G>A, p.(Glu129Lys) variant in GJB2 gene is 0,00385% (4/35432 Latino alleles with 95%CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/) which meets the criteria to apply to PM2 rule. Computational evidence was not enough to neither apply to PP3 nor BP4 since REVEL score was 0.560. The p.(Glu129Lys) change has been identified in heterozygous state in six patients (PMID: 15666300, 17666888, 15964725, 11556849). In addition, it was reported (PMID: 11556849) that this variant could segregate in a dominant mode (data not shown) in patient with unilateral high frequency hearing loss and his affected father. However, since segregation analysis was not performed, this information was not counted. On the other hand, p.(Glu129Lys) has been identified in trans with a presumed pathogenic variant (p.Ala40Gly) (PMID: 19371219) meeting PM3 criteria. In summary, the clinical significance of this variant is currently uncertain (PM2, PM3). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;T;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.72

.;.;T

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Uncertain

0.033

MutationAssessor

Benign

1.7

L;L;L

MutationTaster

Benign

0.99

N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.29

N;N;.

REVEL

Uncertain

0.56

Sift

Benign

0.51

T;T;.

Sift4G

Benign

0.53

T;T;.

Polyphen

0.30

B;B;B

Vest4

0.19

MVP

0.86

MPC

0.042

ClinPred

0.058

GERP RS

4.6

Varity_R

0.36

gMVP

0.85

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