rs274754

Variant names:

• chr1-36100016-G-A
• rs274754
• NM_005202.4:c.193+34C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005202.4(COL8A2):​c.193+34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.732 in 1,595,172 control chromosomes in the GnomAD database, including 442,715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (32609 hom., cov: 33)
  • Exomes 𝑓: 0.74 (410106 hom.)
• Consequence: COL8A2 NM_005202.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.14
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-36100016-G-A is Benign according to our data. Variant chr1-36100016-G-A is described in ClinVar as Benign. ClinVar VariationId is 1255398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL8A2	NM_005202.4	c.193+34C>T		intron_variant	Intron 3 of 3	ENST00000397799.2	NP_005193.1
COL8A2	NM_001294347.2	c.-3+179C>T		intron_variant	Intron 3 of 3		NP_001281276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL8A2	ENST00000397799.2	c.193+34C>T		intron_variant	Intron 3 of 3	5	NM_005202.4	ENSP00000380901.1
COL8A2	ENST00000481785.1	c.-3+179C>T		intron_variant	Intron 1 of 1	1		ENSP00000436433.1
COL8A2	ENST00000303143.9	c.193+34C>T		intron_variant	Intron 1 of 1	2		ENSP00000305913.4

Frequencies

GnomAD3 genomes AF: 0.627 AC: 95262 AN: 151990 Hom.: 32600 Cov.: 33

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.732

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.745

Gnomad NFE AF: 0.793

Gnomad OTH AF: 0.654

GnomAD2 exomes AF: 0.646 AC: 159799 AN: 247318 AF XY: 0.663

Gnomad AFR exome AF: 0.383

Gnomad AMR exome AF: 0.513

Gnomad ASJ exome AF: 0.728

Gnomad EAS exome AF: 0.213

Gnomad FIN exome AF: 0.677

Gnomad NFE exome AF: 0.783

Gnomad OTH exome AF: 0.702

GnomAD4 exome AF: 0.743 AC: 1072296 AN: 1443064 Hom.: 410106 Cov.: 30 AF XY: 0.742 AC XY: 531856 AN XY: 716402

African (AFR) AF: 0.378 AC: 12529 AN: 33148

American (AMR) AF: 0.524 AC: 23334 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.726 AC: 18878 AN: 26020

East Asian (EAS) AF: 0.224 AC: 8827 AN: 39352

South Asian (SAS) AF: 0.642 AC: 55147 AN: 85900

European-Finnish (FIN) AF: 0.685 AC: 36204 AN: 52880

Middle Eastern (MID) AF: 0.715 AC: 3745 AN: 5236

European-Non Finnish (NFE) AF: 0.795 AC: 871393 AN: 1096440

Other (OTH) AF: 0.709 AC: 42239 AN: 59572

GnomAD4 genome AF: 0.627 AC: 95315 AN: 152108 Hom.: 32609 Cov.: 33 AF XY: 0.618 AC XY: 45945 AN XY: 74370

African (AFR) AF: 0.394 AC: 16361 AN: 41488

American (AMR) AF: 0.587 AC: 8965 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.732 AC: 2541 AN: 3470

East Asian (EAS) AF: 0.236 AC: 1219 AN: 5170

South Asian (SAS) AF: 0.616 AC: 2973 AN: 4826

European-Finnish (FIN) AF: 0.670 AC: 7095 AN: 10584

Middle Eastern (MID) AF: 0.747 AC: 218 AN: 292

European-Non Finnish (NFE) AF: 0.793 AC: 53881 AN: 67970

Other (OTH) AF: 0.654 AC: 1382 AN: 2112

Alfa AF: 0.734 Hom.: 164025

Bravo AF: 0.606

Asia WGS AF: 0.485 AC: 1690 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Posterior polymorphous corneal dystrophy 2 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Corneal dystrophy, Fuchs endothelial, 1 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.35
DANN	Benign	0.67
PhyloP100		-2.1
PromoterAI		0.00010	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs274754; hg19: chr1-36565617;