rs80358191

Variant names:

• chr1-36098318-G-T
• rs80358191
• NM_005202.4:c.1363C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2 PM5 PP5 BP4

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
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 1.16
• Publications: 65 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 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 VariationId 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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL8A2	NM_005202.4	MANE Select	c.1363C>A	p.Gln455Lys	missense	Exon 4 of 4	NP_005193.1	P25067
	COL8A2	NM_001294347.2		c.1168C>A	p.Gln390Lys	missense	Exon 4 of 4	NP_001281276.1	E9PP49

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL8A2	ENST00000397799.2	TSL:5 MANE Select	c.1363C>A	p.Gln455Lys	missense	Exon 4 of 4	ENSP00000380901.1	P25067
	COL8A2	ENST00000481785.1	TSL:1	c.1168C>A	p.Gln390Lys	missense	Exon 2 of 2	ENSP00000436433.1	E9PP49
	COL8A2	ENST00000303143.9	TSL:2	c.1363C>A	p.Gln455Lys	missense	Exon 2 of 2	ENSP00000305913.4	P25067

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396180 Hom.: 0 Cov.: 37 AF XY: 0.00000145 AC XY: 1 AN XY: 688604

African (AFR) AF: 0.00 AC: 0 AN: 31546

American (AMR) AF: 0.00 AC: 0 AN: 35824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4480

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078634

Other (OTH) AF: 0.00 AC: 0 AN: 57796

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Corneal dystrophy, Fuchs endothelial, 1 (1)
1	-	-	Posterior polymorphous corneal dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.0059	T
MutationAssessor	Benign	0.84	L
PhyloP100		1.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.55
Sift	Benign	0.90	T
Sift4G	Benign	0.74	T
Polyphen		0.46	P
Vest4		0.21
MutPred		0.77		Gain of ubiquitination at Q455 (P = 0.0085)
MVP		0.93
MPC		0.38
ClinPred		0.32	T
GERP RS		4.4
Varity_R		0.31
gMVP		0.66
Mutation Taster		=17/83	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: rs80358191; hg19: chr1-36563919;