rs786204491

Positions:

chr13-20189291-G-GT

Variant summary

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

The NM_004004.6(GJB2):c.290_291insA(p.Tyr97Ter) variant causes a stop gained, frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,684 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. Y97Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GJB2
NM_004004.6 stop_gained, frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.97

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 106 pathogenic variants in the truncated region.

PP5

Variant 13-20189291-G-GT is Pathogenic according to our data. Variant chr13-20189291-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 188821.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.290_291insA	p.Tyr97Ter	stop_gained, frameshift_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3 linkuse as main transcript	c.290_291insA	p.Tyr97Ter	stop_gained, frameshift_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.290_291insA	p.Tyr97Ter	stop_gained, frameshift_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.290_291insA	p.Tyr97Ter	stop_gained, frameshift_variant	1/1			P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152082

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

251002

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135676

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461602

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727114

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:

0.0000135

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74286

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000187

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Oct 04, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2020	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 130 amino acids are lost, 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: 31589614, 32747562, 15070423, 28405014, 24529908, 19371219, 17935238, 25560255, 11584050, 22695344, 22000900, 25012701, 15488970, 24039984) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 16, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188821). This premature translational stop signal has been observed in individual(s) with autosomal recessive non-syndromic hearing loss (PMID: 11584050, 15070423, 19371219, 22695344). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs786204491, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Tyr97*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 130 amino acid(s) of the GJB2 protein. -

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 28, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 13, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 09, 2017	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2023

The c.290dupA (p.Y97*) alteration, located in exon 2 (coding exon 1) of the GJB2 gene, consists of a duplication of A at position 290. This changes the amino acid from an aspartic acid (D) to a stop codon at amino acid position 97. Premature stop codons are typically deleterious in nature; however, because GJB2 is a single-exon gene this alteration is not expected to trigger nonsense-mediated mRNA decay and a truncated protein could still be expressed (Maquat, 2004). This alteration removes the last 130 amino acids of the protein and the exact functional impact of these amino acids is unknown at this time. _x000D_ _x000D_ _x000D_ _x000D_ for autosomal recessive GJB2-related non-syndromic hearing loss; however, its clinical significance for autosomal dominant GJB2-related non-syndromic hearing loss and autosomal dominant GJB2-related syndromic hearing loss with ectodermal involvement is uncertain._x000D_ _x000D_ _x000D_ _x000D_ Manually add references to AVA4 alteration page for Maquat 2004:_x000D_ _x000D_ _x000D_ 15040442 Based on data from gnomAD, this allele has an overall frequency of 0.001% (4/282386) total alleles studied. The highest observed frequency was 0.003% (4/128904) of European (non-Finnish) alleles. This variant has been identified in the homozygous state or in trans with another GJB2 pathogenic variant in multiple individuals with clinical features of GJB2-related non-syndromic hearing loss (Mustapha, 2001; Abbaspour Rodbaneh, 2021; Bonyadi, 2014). Based on the available evidence, this alteration is classified as pathogenic. -

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

Mar 29, 2022

- -

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