rs727504229

Variant names:

• chr1-36098317-TG-AC
• rs727504229
• NM_005202.4:c.1363_1364delCAinsGT

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. 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. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• Publications: 17 publications found

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]

COL8A2 Gene-Disease associations (from GenCC):

• corneal dystrophy, Fuchs endothelial, 1

  Inheritance: AD Classification: STRONG Submitted by: G2P
• posterior polymorphous corneal dystrophy 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Fuchs' endothelial dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• posterior polymorphous corneal dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• 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 rank	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 rank	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

Apr 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=3/97	disease causing

Splicing

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

Other links and lift over

dbSNP: rs727504229; hg19: chr1-36563918;