rs1555342014

chr13-20189570-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004004.6(GJB2):c.11del(p.Gly4AlafsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GJB2 NM_004004.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.410

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 18 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 271 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-20189570-GC-G is Pathogenic according to our data. Variant chr13-20189570-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496214.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	c.11del	p.Gly4AlafsTer10	frameshift_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.11del	p.Gly4AlafsTer10	frameshift_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.11del	p.Gly4AlafsTer10	frameshift_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.11del	p.Gly4AlafsTer10	frameshift_variant	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2023	This sequence change creates a premature translational stop signal (p.Gly4Alafs*10) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 223 amino acid(s) of the GJB2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 17666888). ClinVar contains an entry for this variant (Variation ID: 496214). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Leu213*) have been determined to be pathogenic (PMID: 23141775). 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	Feb 01, 2022	Observed in a patient with hearing loss in published literature; however, no specific information on the patient is available (Putcha GV et al., 2007); Frameshift variant predicted to result in protein truncation, as the last 223 amino acids are replaced with 9 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17666888) -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 21, 2018

The GJB2 c.11delG; p.Gly4fs variant, also published as 8delG, is reported in the medical literature in at least two individuals with hearing loss (Banjara 2016, Putcha 2007). The variant is reported in the ClinVar database (Variation ID: 496214), but is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, the variant is classified as pathogenic in the Deafness Variation Database (see link below) and other frameshift variants in this region are classified as pathogenic (see link to ClinVar below). Considering available information, this variant is classified as pathogenic. References: Link to Deafness Variation Database: http://deafnessvariationdatabase.org Link to GJB2 in ClinVar: http://www.ncbi.nlm.nih.gov/clinvar/?term=GJB2%5Bgene%5D Banjara H et al. Detection of Connexion 26 GENE (GJB2) Mutations in Cases of Congenital Non Syndromic Deafness. Indian J Otolaryngol Head Neck Surg. 2016 Jun;68(2):248-53. 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. -

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 05, 2016

Variant summary: This GJB2 c.11delG variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 4 and leads to a premature termination codon nine amino acids downstream. Mutation taster predicts this variant to be disease-causing. The variant was not observed in the large and broad cohorts of the ExAC project or ESP. The variant of interest was reported in 2 patients with hearing loss (Putcha_GenMed_2007, Banjara_IJOHNS_2015). Truncations downstream of this position have been classified as disease/pathogenic variants by our laboratory such as c.19C>T (p.Gln7X ), c.35dupG (V13fs), and c.35delG (G12fs). Deafness variation database lists the variant as "pathogenic." Considering all evidence, this variant has been classified as Likely Pathogenic until additional information becomes available. -

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: rs1555342014; hg19: chr13-20763709;