1-36097564-G-A

Variant names:

• chr1-36097564-G-A
• rs149180733
• NM_005202.4:c.*5C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005202.4(COL8A2):​c.*5C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,594,428 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (5 hom.)
• Consequence: COL8A2 NM_005202.4 3_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.20
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BS2: High AC in GnomAd4 at 282 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL8A2	NM_005202.4	c.*5C>T		3_prime_UTR_variant	Exon 4 of 4	ENST00000397799.2	NP_005193.1
COL8A2	NM_001294347.2	c.*5C>T		3_prime_UTR_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.*5C>T		3_prime_UTR_variant	Exon 4 of 4	5	NM_005202.4	ENSP00000380901.1
COL8A2	ENST00000481785.1	c.*5C>T		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000436433.1
COL8A2	ENST00000303143.9	c.*5C>T		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000305913.4

Frequencies

GnomAD3 genomes AF: 0.00186 AC: 282 AN: 151974 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00162 AC: 399 AN: 246100 AF XY: 0.00147

Gnomad AFR exome AF: 0.000764

Gnomad AMR exome AF: 0.000588

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000799

Gnomad NFE exome AF: 0.00307

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00253 AC: 3650 AN: 1442338 Hom.: 5 Cov.: 35 AF XY: 0.00239 AC XY: 1714 AN XY: 716040

African (AFR) AF: 0.00146 AC: 48 AN: 32910

American (AMR) AF: 0.000636 AC: 28 AN: 44042

Ashkenazi Jewish (ASJ) AF: 0.0000390 AC: 1 AN: 25612

East Asian (EAS) AF: 0.00 AC: 0 AN: 39432

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85468

European-Finnish (FIN) AF: 0.000671 AC: 35 AN: 52146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4946

European-Non Finnish (NFE) AF: 0.00313 AC: 3433 AN: 1098256

Other (OTH) AF: 0.00173 AC: 103 AN: 59526

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152090 Hom.: 1 Cov.: 33 AF XY: 0.00168 AC XY: 125 AN XY: 74370

African (AFR) AF: 0.00101 AC: 42 AN: 41380

American (AMR) AF: 0.000915 AC: 14 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00319 AC: 217 AN: 67998

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00238 Hom.: 3

Bravo AF: 0.00191

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

COL8A2-related disorder Benign:1

May 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.026
DANN	Benign	0.89
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism

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: rs149180733; hg19: chr1-36563165;