chr1-36097838-G-T

Variant names:

• chr1-36097838-G-T
• NM_005202.4:c.1843C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005202.4(COL8A2):​c.1843C>A​(p.Pro615Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL8A2 NM_005202.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.23
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL8A2	NM_005202.4	c.1843C>A	p.Pro615Thr	missense_variant	Exon 4 of 4	ENST00000397799.2	NP_005193.1
COL8A2	NM_001294347.2	c.1648C>A	p.Pro550Thr	missense_variant	Exon 4 of 4		NP_001281276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL8A2	ENST00000397799.2	c.1843C>A	p.Pro615Thr	missense_variant	Exon 4 of 4	5	NM_005202.4	ENSP00000380901.1
COL8A2	ENST00000481785.1	c.1648C>A	p.Pro550Thr	missense_variant	Exon 2 of 2	1		ENSP00000436433.1
COL8A2	ENST00000303143.9	c.1843C>A	p.Pro615Thr	missense_variant	Exon 2 of 2	2		ENSP00000305913.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1843C>A (p.P615T) alteration is located in exon 2 (coding exon 2) of the COL8A2 gene. This alteration results from a C to A substitution at nucleotide position 1843, causing the proline (P) at amino acid position 615 to be replaced by a threonine (T). 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	0.11
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;.
Eigen	Benign	-0.020
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	.;T;T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.80	N;N;.
PhyloP100		4.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.51	T;T;T
Polyphen		0.023	B;B;.
Vest4		0.62
MutPred		0.54		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.81
MPC		0.58
ClinPred		0.84	D
GERP RS		4.6
Varity_R		0.21
gMVP		0.77
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr1-36563439;