Genetic Variant NM_005202.4:c.1928C>A (chr1-36097753-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.19

Publications

0 publications found

Variant links:

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

COL8A2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 link	c.1928C>A	p.Pro643Gln	missense_variant	Exon 4 of 4	ENST00000397799.2	NP_005193.1	P25067
COL8A2	NM_001294347.2 link	c.1733C>A	p.Pro578Gln	missense_variant	Exon 4 of 4		NP_001281276.1	P25067E9PP49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL8A2	ENST00000397799.2 link	c.1928C>A	p.Pro643Gln	missense_variant	Exon 4 of 4	5	NM_005202.4	ENSP00000380901.1	P25067
COL8A2	ENST00000481785.1 link	c.1733C>A	p.Pro578Gln	missense_variant	Exon 2 of 2	1		ENSP00000436433.1	E9PP49
COL8A2	ENST00000303143.9 link	c.1928C>A	p.Pro643Gln	missense_variant	Exon 2 of 2	2		ENSP00000305913.4	P25067

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461512

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727068

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.044843), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

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

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

.;D;D

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.78

D;D;D

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.8

L;L;.

PhyloP100

8.2

PrimateAI

Pathogenic

0.82

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

GERP RS

4.9

Varity_R

0.49

gMVP

0.64

Mutation Taster

=34/66

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over