rs727504229

Positions:

• chr1-36098317-TG-AC

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_005202.4(COL8A2):​c.1363_1364delCAinsGT​(p.Gln455Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q455K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL8A2 NM_005202.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.82

Genes affected

COL8A2 (HGNC:2216): (collagen type VIII alpha 2 chain) This gene encodes the alpha 2 chain of type VIII collagen. This protein is a major component of the basement membrane of the corneal endothelium and forms homo- or heterotrimers with alpha 1 (VIII) type collagens. Defects in this gene are associated with Fuchs endothelial corneal dystrophy and posterior polymorphous corneal dystrophy type 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-36098318-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 17147.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 1-36098317-TG-AC is Pathogenic according to our data. Variant chr1-36098317-TG-AC is described in ClinVar as [Pathogenic]. Clinvar id is 167868.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL8A2	NM_005202.4	c.1363_1364delCAinsGT	p.Gln455Val	missense_variant		ENST00000397799.2	NP_005193.1
COL8A2	NM_001294347.2	c.1168_1169delCAinsGT	p.Gln390Val	missense_variant			NP_001281276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL8A2	ENST00000397799.2	c.1363_1364delCAinsGT	p.Gln455Val	missense_variant		5	NM_005202.4	ENSP00000380901.1
COL8A2	ENST00000481785.1	c.1168_1169delCAinsGT	p.Gln390Val	missense_variant		1		ENSP00000436433.1
COL8A2	ENST00000303143.9	c.1363_1364delCAinsGT	p.Gln455Val	missense_variant		2		ENSP00000305913.4

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Corneal dystrophy, Fuchs endothelial, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2009

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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: rs727504229; hg19: chr1-36563918;