rs864309684

Positions:

• chr1-147908040-C-CT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005267.5(GJA8):​c.89dupT​(p.Ile31fs) variant causes a frameshift 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: GJA8 NM_005267.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.95

Genes affected

GJA8 (HGNC:4281): (gap junction protein alpha 8) This gene encodes a transmembrane connexin protein that is necessary for lens growth and maturation of lens fiber cells. The encoded protein is a component of gap junction channels and functions in a calcium and pH-dependent manner. Mutations in this gene have been associated with zonular pulverulent cataracts, nuclear progressive cataracts, and cataract-microcornea syndrome. [provided by RefSeq, Dec 2009]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 94 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-147908040-C-CT is Pathogenic according to our data. Variant chr1-147908040-C-CT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217331.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA8	NM_005267.5	c.89dupT	p.Ile31fs	frameshift_variant	2/2	ENST00000369235.2	NP_005258.2
GJA8	XM_011509417.3	c.89dupT	p.Ile31fs	frameshift_variant	1/2		XP_011507719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA8	ENST00000369235.2	c.89dupT	p.Ile31fs	frameshift_variant	2/2	6	NM_005267.5	ENSP00000358238.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 1 multiple types Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania

Jan 21, 2023

Variant identified and curated during a GJA8 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PVS1(Strong), PM1(Supporting), PM2(Supporting), PP3. Original variant report: PMID:26694549. Additional phenotype/s reported in these individual/s are: secondary glaucoma. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 -

Developmental cataract Pathogenic:1

Pathogenic, no assertion criteria provided

research

Eye Genetics Research Group, Children's Medical Research Institute

Jan 09, 2015

- -

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: rs864309684; hg19: chr1-147380167;