rs34988750

Positions:

chr13-20189104-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6

The NM_004004.6(GJB2):c.478G>A(p.Gly160Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000699 in 1,614,054 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00067 ( 1 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:11

Conservation

PhyloP100: 6.12

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_benign. Variant got -1 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=0.12778345).

BP6

Variant 13-20189104-C-T is Benign according to our data. Variant chr13-20189104-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44755.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=3, Uncertain_significance=11}. Variant chr13-20189104-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.478G>A	p.Gly160Ser	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 linkuse as main transcript	c.478G>A	p.Gly160Ser	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.478G>A	p.Gly160Ser	missense_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.478G>A	p.Gly160Ser	missense_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

154

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000705

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000558

AC:

140

AN:

251098

Hom.:

AF XY:

0.000589

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000617

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000667

AC:

975

AN:

1461786

Hom.:

Cov.:

AF XY:

0.000635

AC XY:

462

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00194

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000711

Gnomad4 OTH exome

AF:

0.000977

GnomAD4 genome

AF:

0.00101

AC:

154

AN:

152268

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00217

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000789

Hom.:

Bravo

AF:

0.00120

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000527

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 16, 2019	The GJB2 c.478G>A; p.Gly160Ser variant (rs34988750) is reported heterozygously in several individuals with hearing loss who also carry one copy of a pathogenic GJB2 variant (Snoeckx 2005), but phase was not reported; however, p.Gly160Ser has also been reported in cis to a pathogenic GJB2 variant in several individuals (Zheng 2015). The p.Gly160Ser variant is found in the African population with an overall allele frequency of 0.22% (55/24922 alleles) in the Genome Aggregation Database and it is reported in ClinVar (Variation ID: 44755). The glycine at codon 160 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical and functional data, the significance of the p.Gly160Ser variant is uncertain at this time. References: Snoeckx RL et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 Dec;77(6):945-57. Zheng J et al. GJB2 Mutation Spectrum and Genotype-Phenotype Correlation in 1067 Han Chinese Subjects with Non-Syndromic Hearing Loss. PLoS One. 2015 Jun 4;10(6):e0128691. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2022	BS1_supporting, PP3 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 08, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2024	Observed in the heterozygous state with no other pathogenic GJB2 variant in many patients with hearing loss in published literature (PMID: 12189487, 14722929, 17041943, 19125024); Variant does not have significant effects on gap junction communication in vitro (PMID: 19230829) and has been considered a benign polymorphism (PMID: 19043807, 12172392); 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: 12172392, 27153395, 16222667, 17660464, 22567861, 17426645, 9600457, 25388846, 25266519, 19043807, 17041943, 12172394, 15365987, 14722929, 19125024, 26043044, 19887791, 24529908, 30245029, 22103400, 16380907, 11313763, 21162657, 33096615, 31992338, 31620696, 31569309, 34338889, 27785406, 12189487, 15070423, 36579563, 22695344, 36048236, 24737404, 30466042, 19230829, 36597107, 19371219, 21366436) -

Autosomal recessive nonsyndromic hearing loss 1A

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 09, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 20, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 12, 2024	Variant summary: GJB2 c.478G>A (p.Gly160Ser) results in a non-conservative amino acid change located in the cysteine-rich domain (IPR019570) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 1622152 control chromosomes including one homozygote, predominantly at a frequency of 0.0021 within the African or African-American subpopulation in the gnomAD database (v4.0.0). TThis frequency is about 85-fold higher than the estimated maximum for a pathogenic variant in GJB2 causing Autosomal Dominant Non-Syndromic Hearing Loss (NSHL) (0.0022 vs. 2.5E-05), that rules out the dominant inheritance mode for the variant. However, this frequency is not higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive NSHL (0.0022 vs. 0.025), allowing no conclusion about variant significance for the recessive mode of inheritance. Additional evidence supporting the benign nature of this variant comes from a study which identified the variant in 7/7401 North American hearing loss patients (Putcha 2007). This represents a lower allele frequency (0.00047) in the North American hearing loss population, than either the highest observed allele frequency (0.0022) or the overall frequency for diverse ethnicities (0.0006) of the variant in the control cohort (in gnomAD). The variant, c.478G>A, has been reported in the literature in several individuals affected with Non-Syndromic Hearing Loss, however in most of these cases there was no second allele identified, and in some cases the variant was also mentioned to be present in heterozygosity in unaffected family member (e.g. Wu 2002, Janecke 2002, Gasmelseed 2004, Azaiez 2004, Cheng 2005, Tang 2006, Primignani 2009, Ji 2011, Koohiyan_2019, Ozylmaz_2019, Abtahi_2020); therefore these reports do not indicate a pathogenic role for the variant. Though the variant was reported to be found in homozygosity in one patient from an inbred family, no further information (i.e. co-segregation or co-occurrence data) was provided (Khalifa Alkowari 2012). In a few cases the variant was found in compound heterozygosity with a (potentially) pathogenic allele in patients; however, the phase of the variants was not confirmed by parental testing (Snoeckx 2005, Zhang 2011, Yu_2020). Moreover, the variant was also found in a compound heterozygote (V37I/G160S) with normal hearing (Roux 2004), arguing against its pathogenicity. At least two NSHL patients, homozygous for the common disease variant c.235delC, were reported to also carry the variant of interest, indicating the variant to be in the benign spectrum (Jiang 2014, Zheng 2015). 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: 15070423, 17041943, 15365987, 16380907, 14722929, 17426645, 12172394, 12189487, 22695344, 16222667, 9600457, 19371219, 17666888, 19043807, 22103400, 21162657, 19235794, 21366436, 19125024, 31992338, 15832357, 26043044, 24737404, 30245029, 30466042, 31569309, 31620696). ClinVar contains an entry for this variant (Variation ID: 44755). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 18, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 17, 2010	Gly160Ser in exon 2 of GJB2: This variant has been identified at a frequency of 0.1-0.5% in several studies of individuals with hearing loss (Janecke 2002, Bati ssoco 2008, Gasmelseed 2004, Ross 2007). However, in none of these individuals w as a second GJB2 variant identified. In addition, this variant has been identifi ed in 3/140 (2%) controls (Scott 1998, rs34988750). In summary, the Gly160Ser va riant is not expected to have clinical or pathological significance due to its o ccurrence at a lower frequency in cases compared to controls. -

Ichthyosis, hystrix-like, with hearing loss

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Autosomal dominant nonsyndromic hearing loss 3A

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Autosomal dominant keratitis-ichthyosis-hearing loss syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Nonsyndromic Deafness

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

May 19, 2017

Reported in gene specific databases (davinci.crg.es/deafness/index.php), ClinVar, and the scientific literature as benign. The evidence for this classification is unclear/not provided, but at least in some cases appears to be due to a reported control population allele frequency of 2% (Scott et al., 1998 PMID: 9600457). This variant is reported in population databases at frequencies of up to 0.22% (gnomAD, ExAC). In silico analyses predict an impact on the protein. -

Nonsyndromic genetic hearing loss

Benign:1

Likely benign, 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 filter allele frequency of c.478G>A, p.(Gly160Ser) is 0,17% (55/24922 African 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 BS1_Supporting criteria. Computational analysis predicted a damage impact of the mutation to the protein (REVELscore:0.767) meeting PP3 rule. The p.(Gly160Ser) change has been identified in heterozygous state in several hearing loss individuals among different ethnic groups (PMID: 24158611, 21162657, 24529908, 19371219, 19125024, 17660464, 16222667, 15070423). This variant has been found in two Austrian familial cases which have been tested only for GJB2 gene: the first case with both parents and child affected in which the proband and her father carried the variant in heterozygous state. The second case is composed of three affected family members: mother and her two daughters. The mother carried p.(Gly160Ser) and her two daughters were not available for the study (PMID: 12189487). Hence, the evidence provided was not enough to apply PP1 rule and was not counted. Besides, this variant has been found in cis with a known pathogenic variant in two unrelated patients (PMID: 22103400) meeting BP2 criteria. Finally, p.(Gly160Ser) change was found with p.Val37Ile and c.35delG in two patients but phase unknown applying to PM3 rule. In summary, this variant meets criteria to be classified as likely benign for autosomal recessive non-syndromic hearing loss (BS1_Supporting, PP3, BP2 and PM3) -

GJB2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;D;D

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

.;.;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

M;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.6

D;D;.

REVEL

Pathogenic

0.77

Sift

Benign

0.060

T;T;.

Sift4G

Uncertain

0.053

T;T;.

Polyphen

0.97

D;D;D

Vest4

0.42

MVP

0.98

MPC

0.20

ClinPred

0.042

GERP RS

5.5

Varity_R

0.60

gMVP

0.92

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