rs767178508

chr13-20189143-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_004004.6(GJB2):c.439G>A(p.Glu147Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,982 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E147G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.86

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_004004.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-20189142-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1312591.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 13-20189143-C-T is Pathogenic according to our data. Variant chr13-20189143-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189143-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.439G>A	p.Glu147Lys	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.439G>A	p.Glu147Lys	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.439G>A	p.Glu147Lys	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.439G>A	p.Glu147Lys	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 251014 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461794 Hom.: 0 Cov.: 33 AF XY: 0.0000344 AC XY: 25 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74340

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:4

Likely pathogenic, no assertion criteria provided	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	Feb 26, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Aug 04, 2017	A heterozygous missense variant was identified, NM_004004.5(GJB2):c.439G>A in exon 2 of the GJB2 gene. This substitution creates a minor amino acid change from a glutamic acid to a lysine at position 147, NP_003995.2(GJB2):p.(Glu147Lys). The glutamic acid at this position has very high conservation (100 vertebrates, UCSC) and in silico predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster).This variant is present in the gnomAD population database at a frequency of 0.001% and it has been previously reported in patients with autosomal recessive deafness (ClinVar, Frei, K. et al. (2004) and Cryns, K. et al. (2004)).It is situated in the third transmembrane domain, which has been shown to be essential for protein function (Frei K. et al. (2004). Based on current information and in association with the NM_004004.5(GJB2):c.35delG deletion variant, this variant has been classified as PATHOGENIC.The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with autosomal recessive deafness. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 147 of the GJB2 protein (p.Glu147Lys). This variant is present in population databases (rs767178508, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 14676473, 21465647, 30168495, 30344259). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 371709). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2023	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: 15253766, 26188157, 25149764, 29921236, 30168495, 29542069, 14676473, 19371219, 14985372, 16380907, 16125251, 17567887, 20022641, 21465647, 26346709, 25388846, 26043044, 30094485, 31215297, 30989077, 30344259, 21131880, 31160754, 30275481, 32645618, 33096615, 31589614, 29871260, 31541171, 31827275) -

Nonsyndromic genetic hearing loss Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	INGEBI, INGEBI / CONICET	Aug 21, 2020	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.439G>A, p.(Glu147Lys) was observed only once in South Asian, Latino and European non-Finnish populations from Genome Aggregation Database (http://gnomad.broadinstitute.org), meeting PM2 criteria. This was detected in trans with at least 4 different pathogenic variants applying to PM3_VeryStrong rule (PMID: 14676473, 21131880, 14985372, 21465647, 26043044). Besides, it segregated in three affected siblings with congenital moderate-profound hearing loss meeting PP1_Moderate criteria (PMID:14676473). Computational evidence predicted a damage impact of the mutation to the protein (REVEL score: 0,94; PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2, PM3_VeryStrong, PP1_Moderate and PP3. -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	May 11, 2022	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 15, 2016

- -

Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 18, 2016

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 21, 2018

The p.Glu147Lys variant in GJB2 has been reported in 8 individuals with hearing loss, including 3 homozygotes and 5 individuals who were compound heterozygous f or a second pathogenic variant (Cryns 2004, de Oliveira 2007, Dodson 2011, Frei 2004, Gravina 2010, Lin 2011, Snoeckx 2005, Zheng 2015). In addition, the varian t segregated in the homozygous state in two affected siblings in one family (Fre i 2004). This variant is present in 3/245794 total chromosomes by gnomAD (http:/ /gnomad.broadinstitute.org), which is low enough to be consistent with a recessi ve carrier frequency. Computational prediction tools and conservation analysis s uggest an impact to the protein. In summary, this variant meets criteria to be c lassified as pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3_VeryStrong, PM2, PP1_Moderate, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;D
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.6	D;D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.99
MutPred		0.88		Gain of MoRF binding (P = 0.01);Gain of MoRF binding (P = 0.01);Gain of MoRF binding (P = 0.01);
MVP		0.99
MPC		0.29
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.99

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

Other links and lift over

dbSNP: rs767178508; hg19: chr13-20763282;