1-36097555-A-AC

Variant names:

• chr1-36097555-A-AC
• rs201628588
• NM_005202.4:c.*13dupG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_005202.4(COL8A2):​c.*13dupG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,573,498 control chromosomes in the GnomAD database, including 17 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0066 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (10 hom.)
• Consequence: COL8A2 NM_005202.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.763
• Publications: 1 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.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00656 (995/151570) while in subpopulation AFR AF = 0.0205 (843/41096). AF 95% confidence interval is 0.0194. There are 7 homozygotes in GnomAd4. There are 466 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 995 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL8A2	NM_005202.4	c.*13dupG		3_prime_UTR_variant	Exon 4 of 4	ENST00000397799.2	NP_005193.1
COL8A2	NM_001294347.2	c.*13dupG		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.*13dupG		3_prime_UTR_variant	Exon 4 of 4	5	NM_005202.4	ENSP00000380901.1
COL8A2	ENST00000481785.1	c.*13dupG		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000436433.1
COL8A2	ENST00000303143.9	c.*13dupG		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000305913.4

Frequencies

GnomAD3 genomes AF: 0.00656 AC: 993 AN: 151454 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00303

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00428

Gnomad SAS AF: 0.00395

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00432

GnomAD2 exomes AF: 0.00283 AC: 681 AN: 240424 AF XY: 0.00265

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.00844

Gnomad EAS exome AF: 0.00316

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.00206

GnomAD4 exome AF: 0.00126 AC: 1787 AN: 1421928 Hom.: 10 Cov.: 25 AF XY: 0.00124 AC XY: 874 AN XY: 706034

African (AFR) AF: 0.0231 AC: 749 AN: 32384

American (AMR) AF: 0.00249 AC: 108 AN: 43400

Ashkenazi Jewish (ASJ) AF: 0.00894 AC: 225 AN: 25154

East Asian (EAS) AF: 0.00181 AC: 71 AN: 39272

South Asian (SAS) AF: 0.00397 AC: 335 AN: 84460

European-Finnish (FIN) AF: 0.0000579 AC: 3 AN: 51826

Middle Eastern (MID) AF: 0.00126 AC: 6 AN: 4748

European-Non Finnish (NFE) AF: 0.000136 AC: 147 AN: 1082022

Other (OTH) AF: 0.00244 AC: 143 AN: 58662

GnomAD4 genome AF: 0.00656 AC: 995 AN: 151570 Hom.: 7 Cov.: 33 AF XY: 0.00629 AC XY: 466 AN XY: 74088

African (AFR) AF: 0.0205 AC: 843 AN: 41096

American (AMR) AF: 0.00302 AC: 46 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.00429 AC: 22 AN: 5126

South Asian (SAS) AF: 0.00396 AC: 19 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67976

Other (OTH) AF: 0.00427 AC: 9 AN: 2106

Alfa AF: 0.00157 Hom.: 0

Asia WGS AF: 0.00462 AC: 16 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.76
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: rs201628588; hg19: chr1-36563156; COSMIC: COSV57443896; COSMIC: COSV57443896;