1-36097753-G-T

Variant names:

• chr1-36097753-G-T
• rs550694898
• NM_005202.4:c.1928C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005202.4(COL8A2):​c.1928C>A​(p.Pro643Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P643L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COL8A2 NM_005202.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.19

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL8A2	NM_005202.4	c.1928C>A	p.Pro643Gln	missense_variant	Exon 4 of 4	ENST00000397799.2	NP_005193.1
COL8A2	NM_001294347.2	c.1733C>A	p.Pro578Gln	missense_variant	Exon 4 of 4		NP_001281276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL8A2	ENST00000397799.2	c.1928C>A	p.Pro643Gln	missense_variant	Exon 4 of 4	5	NM_005202.4	ENSP00000380901.1
COL8A2	ENST00000481785.1	c.1733C>A	p.Pro578Gln	missense_variant	Exon 2 of 2	1		ENSP00000436433.1
COL8A2	ENST00000303143.9	c.1928C>A	p.Pro643Gln	missense_variant	Exon 2 of 2	2		ENSP00000305913.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461512 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 727068

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.54
Sift	Benign	0.059	T;T;T
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.97	D;D;.
Vest4		0.73
MutPred		0.48		Gain of catalytic residue at P643 (P = 0.0127);Gain of catalytic residue at P643 (P = 0.0127);.;
MVP		0.69
MPC		0.99
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.49
gMVP		0.64

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: rs550694898; hg19: chr1-36563354;