chr13-20188931-ATATC-A

Position:

• chr13-20188931-ATATC-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_004004.6(GJB2):​c.647_650delGATA​(p.Arg216fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,444 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: GJB2 NM_004004.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 2.24

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 10 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. Fraction of 0.0499 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PP5: Variant 13-20188931-ATATC-A is Pathogenic according to our data. Variant chr13-20188931-ATATC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 158609.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	c.647_650delGATA	p.Arg216fs	frameshift_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.647_650delGATA	p.Arg216fs	frameshift_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.647_650delGATA	p.Arg216fs	frameshift_variant	2/2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.647_650delGATA	p.Arg216fs	frameshift_variant	1/1	6		ENSP00000372295.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000481 AC: 12 AN: 249266 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461240 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 726916

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000291

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

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

Bravo AF: 0.0000340

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2024	Frameshift variant predicted to result in protein elongation, as the last 11 amino acids are replaced with 16 different amino acids.; This variant is associated with the following publications: (PMID: 15365987, 17041943, 11102979, 25288386, 31160754, 17666888) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 10, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 11, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 21, 2021	The GJB2 c.647_650delGATA; p.Arg216IlefsTer17 variant (rs587783647), also known as c.645_648delTAGA, is reported in the literature in the compound heterozygous state in multiple individuals affected with autosomal-recessive nonsyndromic hearing loss (Azaiez 2004, Hernandez-Juarez 2014, Prasad 2000, Putcha 2007, Tang 2006). This variant is reported as pathogenic or likely pathogenic by multiple laboratories in ClinVar (Variation ID: 158609), and is found in the Latino population with an allele frequency of 0.035% (12/34560 alleles) in the Genome Aggregation Database. This variant results in a premature termination codon in the last exon of the GJB2 gene. While this may not lead to nonsense-mediated decay, it is expected to create an altered protein that would include a sequence of 17 amino acid residues not usually present. Furthermore, functional analyses show that small deletions or additions to the C-terminus of the protein affect channel function (Locke 2011). Based on available information, this variant is considered to be pathogenic. References: Azaiez H et al. GJB2: the spectrum of deafness-causing allele variants and their phenotype. Hum Mutat. 2004 Oct;24(4):305-11. Hernandez-Juarez AA et al. GJB2 and GJB6 mutations are an infrequent cause of autosomal-recessive nonsyndromic hearing loss in residents of Mexico. Int J Pediatr Otorhinolaryngol. 2014 Dec;78(12):2107-12. Locke D et al. Mechanism for modulation of gating of connexin26-containing channels by taurine. J Gen Physiol. 2011 Sep;138(3):321-39. Prasad S et al. Genetic testing for hereditary hearing loss: connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA). Hum Mutat. 2000 Dec;16(6):502-8. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. Tang HY et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A. 2006 Nov 15;140(22):2401-15. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2023	This sequence change creates a premature translational stop signal (p.Arg216Ilefs*17) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs587783647, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with autosomal recessive sensorineural deafness (PMID: 11102979, 17041943, 17666888, 25288386). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.645-648delTAGA. ClinVar contains an entry for this variant (Variation ID: 158609). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 09, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 09, 2024	Variant summary: GJB2 c.647_650delGATA (p.Arg216IlefsX17) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 4.8e-05 in 250054 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (4.8e-05 vs 0.025), allowing no conclusion about variant significance. c.647_650delGATA has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (examples: Prasad_2000, Tang_2006, Putcha_2007). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11102979, 17666888, 17041943). ClinVar contains an entry for this variant (Variation ID: 158609). Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2018

- -

Hearing impairment Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 05, 2021

The p.Arg216fs variant in GJB2 has been previously reported in at least 8 individuals with hearing loss, at least 4 of which were compound heterozygous for a second pathogenic variant in GJB2 (Prasad 2000 PMID: 11102979, Tang 2006 PMID: 17041943, Putcha 2007 PMID: 17666888, Hernandez-Juarez 2014 PMID: 25288386). This variant has also been reported as c.645_648delTAGA in the literature. It has also been identified in 0.03% (12/34560) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 158609). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 216 and leads to a new termination codon 17 amino acids downstream, thus resulting in a longer protein (the abnormal protein is 5 amino acids longer than the normal protein). This variant is expected to disrupt the normal function of the protein; however additional data is needed to confirm this. In summary, the p.Arg216fs variant is pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP Criteria applied: PM3_Very Strong, PM4, PM2_Supporting. -

Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jun 21, 2016

- -

GJB2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 2024

The GJB2 c.647_650delGATA variant is predicted to result in a frameshift and premature protein termination (p.Arg216Ilefs*17). This variant has been reported as causative for autosomal recessive deafness (also described as c.645_648delGATA; Prasad et al 2000. PubMed ID: 11102979; Azaiez et al 2004. PubMed ID: 15365987; Putcha et al 2007. PubMed ID: 17666888). This variant is reported in 0.035% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in GJB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs587783647; hg19: chr13-20763070;