chr1-36098176-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005202.4(COL8A2):c.1505C>T(p.Thr502Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00979 in 1,520,000 control chromosomes in the GnomAD database, including 1,061 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 158 hom., cov: 33)

Exomes 𝑓: 0.0091 ( 903 hom. )

Consequence

COL8A2
NM_005202.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.66

Publications

18 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017183721).

BP6

Variant 1-36098176-G-A is Benign according to our data. Variant chr1-36098176-G-A is described in ClinVar as Benign. ClinVar VariationId is 1287683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL8A2	NM_005202.4 link	c.1505C>T	p.Thr502Met	missense_variant	Exon 4 of 4	ENST00000397799.2	NP_005193.1	P25067
COL8A2	NM_001294347.2 link	c.1310C>T	p.Thr437Met	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.1505C>T	p.Thr502Met	missense_variant	Exon 4 of 4	5	NM_005202.4	ENSP00000380901.1	P25067
COL8A2	ENST00000481785.1 link	c.1310C>T	p.Thr437Met	missense_variant	Exon 2 of 2	1		ENSP00000436433.1	E9PP49
COL8A2	ENST00000303143.9 link	c.1505C>T	p.Thr502Met	missense_variant	Exon 2 of 2	2		ENSP00000305913.4	P25067

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2434

AN:

151690

Hom.:

158

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00827

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0273

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.232

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.0267

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00179

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.0299

AC:

3798

AN:

127074

AF XY:

0.0270

show subpopulations

Gnomad AFR exome

AF:

0.00680

Gnomad AMR exome

AF:

0.0387

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.239

Gnomad FIN exome

AF:

0.0285

Gnomad NFE exome

AF:

0.00149

Gnomad OTH exome

AF:

0.0208

GnomAD4 exome

AF:

0.00910

AC:

12444

AN:

1368192

Hom.:

903

Cov.:

AF XY:

0.00892

AC XY:

6001

AN XY:

672584

show subpopulations

African (AFR)

AF:

0.00738

AC:

226

AN:

30630

American (AMR)

AF:

0.0397

AC:

1304

AN:

32818

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

24248

East Asian (EAS)

AF:

0.202

AC:

7132

AN:

35352

South Asian (SAS)

AF:

0.00790

AC:

619

AN:

78354

European-Finnish (FIN)

AF:

0.0254

AC:

997

AN:

39274

Middle Eastern (MID)

AF:

0.00550

AC:

AN:

4002

European-Non Finnish (NFE)

AF:

0.000956

AC:

1020

AN:

1066992

Other (OTH)

AF:

0.0198

AC:

1117

AN:

56522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

683

1367

2050

2734

3417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

166

332

498

664

830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0161

AC:

2438

AN:

151808

Hom.:

158

Cov.:

AF XY:

0.0181

AC XY:

1345

AN XY:

74200

show subpopulations

African (AFR)

AF:

0.00825

AC:

342

AN:

41452

American (AMR)

AF:

0.0279

AC:

426

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.232

AC:

1179

AN:

5086

South Asian (SAS)

AF:

0.0114

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0267

AC:

283

AN:

10600

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00179

AC:

121

AN:

67776

Other (OTH)

AF:

0.0142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

106

212

318

424

530

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00502

Hom.:

Bravo

AF:

0.0176

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ExAC

AF:

0.0123

AC:

1168

Asia WGS

AF:

0.0990

AC:

343

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 25, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

COL8A2-related disorder

Benign:1

Sep 10, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.11

T;T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.53

.;T;T

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.065

N;N;.

PhyloP100

1.7

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.47

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.27

T;T;T

Sift4G

Benign

0.22

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.035

MPC

0.31

ClinPred

0.0059

GERP RS

3.0

Varity_R

0.020

gMVP

0.16

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over