chr1-36098332-A-C

Variant names:

• chr1-36098332-A-C
• rs80358192
• NM_005202.4:c.1349T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_005202.4(COL8A2):​c.1349T>G​(p.Leu450Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,398,282 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: COL8A2 NM_005202.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.879
• Publications: 62 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-36098332-A-C is Pathogenic according to our data. Variant chr1-36098332-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 17148.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005202.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL8A2	NM_005202.4	MANE Select	c.1349T>G	p.Leu450Trp	missense	Exon 4 of 4	NP_005193.1
	COL8A2	NM_001294347.2		c.1154T>G	p.Leu385Trp	missense	Exon 4 of 4	NP_001281276.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL8A2	ENST00000397799.2	TSL:5 MANE Select	c.1349T>G	p.Leu450Trp	missense	Exon 4 of 4	ENSP00000380901.1
	COL8A2	ENST00000481785.1	TSL:1	c.1154T>G	p.Leu385Trp	missense	Exon 2 of 2	ENSP00000436433.1
	COL8A2	ENST00000303143.9	TSL:2	c.1349T>G	p.Leu450Trp	missense	Exon 2 of 2	ENSP00000305913.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 151672 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1398282 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 689900

African (AFR) AF: 0.00 AC: 0 AN: 31602

American (AMR) AF: 0.00 AC: 0 AN: 36228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35840

South Asian (SAS) AF: 0.00 AC: 0 AN: 79328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4622

European-Non Finnish (NFE) AF: 0.00000370 AC: 4 AN: 1079660

Other (OTH) AF: 0.00 AC: 0 AN: 57882

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

Mar 28, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Corneal dystrophy, Fuchs endothelial, 1 Pathogenic:1

Mar 28, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.027
Eigen_PC	Benign	0.000047
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.085	D
MutationAssessor	Benign	2.0	M
PhyloP100		0.88
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.018	D
Polyphen		0.93	P
Vest4		0.34
MutPred		0.74		Loss of catalytic residue at L450 (P = 0.0892)
MVP		0.95
MPC		0.50
ClinPred		0.20	T
GERP RS		4.4
Varity_R		0.090
gMVP		0.47
Mutation Taster		=15/85	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80358192; hg19: chr1-36563933;