1-36097982-C-T

Position:

chr1-36097982-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_005202.4(COL8A2):c.1699G>A(p.Gly567Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000777 in 1,605,434 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00077 ( 5 hom. )

Consequence

COL8A2
NM_005202.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.29

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01668033).

BP6

Variant 1-36097982-C-T is Benign according to our data. Variant chr1-36097982-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1533975.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}. Variant chr1-36097982-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 121 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL8A2	NM_005202.4 linkuse as main transcript	c.1699G>A	p.Gly567Ser	missense_variant	4/4	ENST00000397799.2	NP_005193.1
COL8A2	NM_001294347.2 linkuse as main transcript	c.1504G>A	p.Gly502Ser	missense_variant	4/4		NP_001281276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
COL8A2	ENST00000397799.2 linkuse as main transcript	c.1699G>A	p.Gly567Ser	missense_variant	4/4	5	NM_005202.4	ENSP00000380901	P2
COL8A2	ENST00000481785.1 linkuse as main transcript	c.1504G>A	p.Gly502Ser	missense_variant	2/2	1		ENSP00000436433	A2
COL8A2	ENST00000303143.9 linkuse as main transcript	c.1699G>A	p.Gly567Ser	missense_variant	2/2	2		ENSP00000305913	P2

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

121

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000985

AC:

231

AN:

234570

Hom.:

AF XY:

0.000950

AC XY:

122

AN XY:

128380

show subpopulations

Gnomad AFR exome

AF:

0.000735

Gnomad AMR exome

AF:

0.00167

Gnomad ASJ exome

AF:

0.00361

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000267

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000977

Gnomad OTH exome

AF:

0.00291

GnomAD4 exome

AF:

0.000775

AC:

1126

AN:

1453148

Hom.:

Cov.:

AF XY:

0.000797

AC XY:

576

AN XY:

722926

show subpopulations

Gnomad4 AFR exome

AF:

0.000419

Gnomad4 AMR exome

AF:

0.00154

Gnomad4 ASJ exome

AF:

0.00288

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000501

Gnomad4 FIN exome

AF:

0.0000209

Gnomad4 NFE exome

AF:

0.000660

Gnomad4 OTH exome

AF:

0.00168

GnomAD4 genome

AF:

0.000795

AC:

121

AN:

152286

Hom.:

Cov.:

AF XY:

0.000725

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00119

Hom.:

Bravo

AF:

0.00104

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.000751

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 05, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2021

The c.1699G>A (p.G567S) alteration is located in exon 2 (coding exon 2) of the COL8A2 gene. This alteration results from a G to A substitution at nucleotide position 1699, causing the glycine (G) at amino acid position 567 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;T;.

Eigen

Benign

0.063

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.85

.;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Uncertain

0.37

MutationAssessor

Benign

0.46

N;N;.

MutationTaster

Benign

0.95

D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.92

N;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.17

T;T;T

Sift4G

Benign

0.23

T;T;T

Polyphen

0.30

B;B;.

Vest4

0.41

MVP

0.65

MPC

0.57

ClinPred

0.014

GERP RS

4.2

Varity_R

0.11

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over