Variant rs80358191 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2PM5PP5BP4

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

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 1.16

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:

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ACMG classification

Classification made for transcript

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	Protein	UniProt
COL8A2	NM_005202.4 linkuse as main transcript	c.1363C>A	p.Gln455Lys	missense_variant	4/4	ENST00000397799.2	NP_005193.1	P25067
COL8A2	NM_001294347.2 linkuse as main transcript	c.1168C>A	p.Gln390Lys	missense_variant	4/4		NP_001281276.1	P25067E9PP49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL8A2	ENST00000397799.2 linkuse as main transcript	c.1363C>A	p.Gln455Lys	missense_variant	4/4	5	NM_005202.4	ENSP00000380901.1	P25067
COL8A2	ENST00000481785.1 linkuse as main transcript	c.1168C>A	p.Gln390Lys	missense_variant	2/2	1		ENSP00000436433.1	E9PP49
COL8A2	ENST00000303143.9 linkuse as main transcript	c.1363C>A	p.Gln455Lys	missense_variant	2/2	2		ENSP00000305913.4	P25067

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1396180

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

688604

show subpopulations

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

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

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.17

T;T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.89

.;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Uncertain

-0.0059

MutationAssessor

Benign

0.84

L;L;.

PrimateAI

Uncertain

0.56

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

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

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