chr13-20189344-G-A

Position:

chr13-20189344-G-A

Variant summary

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

The ENST00000382848.5(GJB2):c.238C>T(p.Gln80Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,160 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 (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

GJB2
ENST00000382848.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

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 144 pathogenic variants in the truncated region.

PP5

Variant 13-20189344-G-A is Pathogenic according to our data. Variant chr13-20189344-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.238C>T	p.Gln80Ter	stop_gained	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 linkuse as main transcript	c.238C>T	p.Gln80Ter	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.238C>T	p.Gln80Ter	stop_gained	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.238C>T	p.Gln80Ter	stop_gained	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251380

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000272

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	This sequence change creates a premature translational stop signal (p.Gln80) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 147 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs199883710, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive deafness (PMID: 17041943, 30168495). ClinVar contains an entry for this variant (Variation ID: 371685). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.His100Argfs14) have been determined to be pathogenic (PMID: 10633133, 12111646, 20083784, 22991996, 24341454, 26043044, 27610647). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2024	Nonsense variant predicted to result in protein truncation, as the last 147 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 30168495, 16950989, 17666888, 25087612, 30473554, 17041943, 36048236) -

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Sep 09, 2016

- -

Nonsyndromic genetic hearing loss

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 06, 2024

Variant summary: GJB2 c.238C>T (p.Gln80X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. The variant allele was found at a frequency of 8e-06 in 251380 control chromosomes. c.238C>T has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss (Putcha_2007, Singh_2018, Tang_2006). The following publications have been ascertained in the context of this evaluation (PMID: 17666888, 30168495, 17041943). ClinVar contains an entry for this variant (Variation ID: 371685). Based on the evidence outlined above, the variant was classified as pathogenic. -

Autosomal dominant nonsyndromic hearing loss 3A

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Sep 09, 2016

- -

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

1.3

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

D;D

Vest4

0.94

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