rs80358191

chr1-36098318-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PM5 PP5 BP4

The NM_005202.4(COL8A2):c.1363C>A(p.Gln455Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. Q455V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: COL8A2 NM_005202.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 1.16

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-36098317-TG-AC is described in ClinVar as [Pathogenic]. Clinvar id is 167868.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 1-36098318-G-T is Pathogenic according to our data. 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28936315).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL8A2	NM_005202.4	c.1363C>A	p.Gln455Lys	missense_variant	4/4	ENST00000397799.2
COL8A2	NM_001294347.2	c.1168C>A	p.Gln390Lys	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL8A2	ENST00000397799.2	c.1363C>A	p.Gln455Lys	missense_variant	4/4	5	NM_005202.4	P2
COL8A2	ENST00000481785.1	c.1168C>A	p.Gln390Lys	missense_variant	2/2	1		A2
COL8A2	ENST00000303143.9	c.1363C>A	p.Gln455Lys	missense_variant	2/2	2		P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396180 Hom.: 0 Cov.: 37 AF XY: 0.00000145 AC XY: 1 AN XY: 688604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Posterior polymorphous corneal dystrophy 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2012

- -

Corneal dystrophy, Fuchs endothelial, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	20
Dann	Benign	0.88
DEOGEN2	Benign	0.17	T;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Uncertain	-0.0059	T
MutationAssessor	Benign	0.84	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.79	N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.90	T;T;T
Sift4G	Benign	0.74	T;T;T
Polyphen		0.46	P;P;.
Vest4		0.21
MutPred		0.77		Gain of ubiquitination at Q455 (P = 0.0085);Gain of ubiquitination at Q455 (P = 0.0085);.;
MVP		0.93
MPC		0.38
ClinPred		0.32	T
GERP RS		4.4
Varity_R		0.31
gMVP		0.66

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: rs80358191; hg19: chr1-36563919;