rs730880338

chr13-20189312-T-TA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_004004.6(GJB2):c.269_270insT(p.Val91SerfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000489 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L90L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

GJB2
NM_004004.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.27

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 Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 118 pathogenic variants in the truncated region.

PP5

Variant 13-20189312-T-TA is Pathogenic according to our data. Variant chr13-20189312-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 177737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.269_270insT	p.Val91SerfsTer11	frameshift_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3 linkuse as main transcript	c.269_270insT	p.Val91SerfsTer11	frameshift_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.269_270insT	p.Val91SerfsTer11	frameshift_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.269_270insT	p.Val91SerfsTer11	frameshift_variant	1/1			P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152150

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251282

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000527

AC:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000603

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 09, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 23, 2016	Variant summary: The GJB2 c.269dupT (p.Val91Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.290dupA, c.298delC, and c.313_326delAAGTTCATCAAGGG). This variant was observed in the large, broad control population, ExAC, with an allele frequency of 2/121348 (1/60674), which does not exceed the estimated maximal expected allele frequency for a pathogenic GJB2 variant of 1/40 (0.025). The variant of interest has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Val91Serfs11) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 136 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs730880338, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with severe hearing loss and autosomal recessive deafness (PMID: 10218527, 11102979, 24158611). It has also been observed to segregate with disease in related individuals. This variant is also known as 269insT. ClinVar contains an entry for this variant (Variation ID: 177737). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Cys211Leufs5) have been determined to be pathogenic (PMID: 9529365, 12910486, 20863150). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2021	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 136 amino acids are lost and replaced with 10 incorrect amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 33297549, 31589614, 33096615, 31160754, 10218527, 24158611) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 14, 2021	- -

Nonsyndromic genetic hearing loss

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Apr 27, 2023	- -
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 filtering allele frquency of c.269dup (p.Val91Serfs*11) variant in the GJB2 gene is 0,0012% (4/113654 european non-finnish chromosomes with 95% CI) in Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the PM2 criteria. The c.269dup variant is predicted to cause a premature stop codon in the only exon of GJB2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in trans with 35delG variant in at least 10 hearing loss patients (PMID: 102185257, 11102979, 11977173, 17146393, 20022641, 20553101, 23555729, 24158611) applying to PM3_VerySrong. The c.269dupT/35delG genotype segregated correctly in three affected siblings (Laboratory of Physiology and Genetics of Hearing, INGEBI internal data) meeting PP1_Moderate rule. Therefore, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PM2, PVS1, PM3_VerySrong, PP1_Moderate) -

Hearing loss

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Dec 17, 2015

- -

Nonsyndromic Deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Nov 23, 2018

- -

Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1844678:X-linked mixed hearing loss with perilymphatic gusher;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 24, 2022

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 07, 2015

The p.Val91fs (c.269_270insT) variant in GJB2 has been reported in over 10 indiv iduals with hearing loss who were homozygous or compound heterozygous for a know n pathogenic variant (Dahl 2013, Dalamon 2013, Denoyelle 1999, Gravina 2010, Gre en 1999, Pandya 2003, Preciado 2004, Propst 2006, Siem 2010, Snoeckx 2005). Thi s variant has been identified in 2/66710 of European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org); though this frequen cy is low enough to be consistent with a recessive carrier frequency. This varia nt is predicted to cause a frameshift, which alters the protein?s amino acid seq uence beginning at position 91 and leads to a premature termination codon 11 ami no acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the GJB2 gene is an establish ed disease mechanism in autosomal recessive sensorineural hearing loss. In summ ary, this variant meets criteria to be classified as pathogenic for autosomal re cessive hearing loss based on predicted impact to the protein and prior reports of the variant in trans with a known pathogenic variant. ACMG/AMP Criteria appli ed: PVS1, PM3_VeryStrong, PM2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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