13-20189519-TCCAATGCTGGTG-TT

Position:

• chr13-20189519-TCCAATGCTGGTG-TT

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.51_62delCACCAGCATTGGinsA​(p.Thr18fs) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJB2 NM_004004.6 frameshift, missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.94

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 77 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-20189520-CCAATGCTGGTG-T is Pathogenic according to our data. Variant chr13-20189520-CCAATGCTGGTG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17013.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.51_62delCACCAGCATTGGinsA	p.Thr18fs	frameshift_variant, missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.51_62delCACCAGCATTGGinsA	p.Thr18fs	frameshift_variant, missense_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.51_62delCACCAGCATTGGinsA	p.Thr18fs	frameshift_variant, missense_variant	2/2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.51_62delCACCAGCATTGGinsA	p.Thr18fs	frameshift_variant, missense_variant	1/1	6		ENSP00000372295.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2000

- -

Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 17, 2024

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 27, 2022

This variant is expected to result in the loss of a functional protein. This variant appears to segregate with autosomal recessive nonsyndromic hearing loss and deafness in at least one family. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886037624; hg19: chr13-20763659;