rs111033297

Positions:

chr13-20189413-G-A

Variant summary

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

The ENST00000382848.5(GJB2):c.169C>T(p.Gln57Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000906 in 1,612,288 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q57Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

GJB2
ENST00000382848.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 9.94

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 189 pathogenic variants in the truncated region.

PP5

Variant 13-20189413-G-A is Pathogenic according to our data. Variant chr13-20189413-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 44725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189413-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.169C>T	p.Gln57Ter	stop_gained	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 linkuse as main transcript	c.169C>T	p.Gln57Ter	stop_gained	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.169C>T	p.Gln57Ter	stop_gained	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.169C>T	p.Gln57Ter	stop_gained	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152224

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251022

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135644

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:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000973

AC:

142

AN:

1460064

Hom.:

Cov.:

AF XY:

0.0000785

AC XY:

AN XY:

725936

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.000122

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74376

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000721

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	Jun 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 19, 2021	Variant summary: GJB2 c.169C>T (p.Gln57X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant allele was found at a frequency of 2.8e-05 in 251022 control chromosomes. c.169C>T has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (e.g. Wilcox_1999, Roux_2004, Snoeckx_2005, Marlin_2005). These data indicate that the variant is very likely to be associated with disease. Seven 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 09, 2015	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 11, 2022	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). In multiple individuals affected with hearing loss, this variant has been seen with a single recessive pathogenic variant in the same gene. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 19, 2017	The p.Gln57Ter (rs111033297) has been observed in several cohorts of patients with sensorineural hearing loss, many carrying a second pathogenic variant in GJB2 (selected references: Wilcox 1999, Snoeckx 2005, Marlin 2005). This variant introduces a premature termination codon and is predicted to result in a truncated protein product. Consistent with a recessive carrier frequency, it is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.004% (identified in 11 out of 276,670 chromosomes). It is also listed in the ClinVar database as pathogenic (Variation ID: 44725). Thus, the p.Gln57Ter variant satisfies our criteria for classification as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2023	This sequence change creates a premature translational stop signal (p.Gln57) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 170 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs111033297, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with clinical features of GJB2-related deafness (PMID: 10353784, 21465647). ClinVar contains an entry for this variant (Variation ID: 44725). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Tyr65) have been determined to be pathogenic (PMID: 9482292, 16380907). 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	Jun 18, 2024	Nonsense variant predicted to result in protein truncation, as the last 170 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 26940866, 15547423, 18196482, 21298644, 25270357, 9482292, 25087612, 10353784, 21465647, 15150777, 16380907, 11439000, 15070423, 18324688, 20553101, 15365987, 17041943, 29106882, 29625052, 26689913, 31980526, 31589614, 15967879, 36048236, 36451132) -

Hearing loss

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Nov 12, 2009

- -

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

May 09, 2022

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 25, 2007

The Gln57X variant in GJB2 has been reported in at least 20 individuals with hea ring loss (Dodson 2011, Feldmann 2004, Marlin 2005, Roux 2004, Snoeckx 2005, Wil cox 1999). Most of these individuals were homozygous or compound heterozygous. I t has also been identified in 0.007% (9/128912) of European chromosomes by gnomA D (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 57, which is predicted to lead to a truncated or absent protein. Loss of function of the GJB2 gene is an established disease mech anism in autosomal recessive hearing loss. In summary, this variant meets criter ia to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PM2. -

GJB2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2024

The GJB2 c.169C>T variant is predicted to result in premature protein termination (p.Gln57*). This variant has been reported in multiple individuals with autosomal recessive deafness (Wilcox. 1999. PubMed ID: 10353784; Dodson. 2011. PubMed ID: 21465647; Snoeckx. 2005. PubMed ID: 16380907; Marlin. 2005. PubMed ID: 15967879). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in GJB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

D;D

Vest4

0.93

GERP RS

5.3

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