rs274754

Positions:

• chr1-36100016-G-A

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: -2.14

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
COL8A2	NM_005202.4	c.193+34C>T		intron_variant		ENST00000397799.2
COL8A2	NM_001294347.2	c.-3+179C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL8A2	ENST00000397799.2	c.193+34C>T		intron_variant		5	NM_005202.4	P2
COL8A2	ENST00000481785.1	c.-3+179C>T		intron_variant		1		A2
COL8A2	ENST00000303143.9	c.193+34C>T		intron_variant		2		P2

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

GnomAD3 exomes AF: 0.646 AC: 159799 AN: 247318 Hom.: 55581 AF XY: 0.663 AC XY: 88969 AN XY: 134176

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 SAS exome AF: 0.640

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

Gnomad4 AFR exome AF: 0.378

Gnomad4 AMR exome AF: 0.524

Gnomad4 ASJ exome AF: 0.726

Gnomad4 EAS exome AF: 0.224

Gnomad4 SAS exome AF: 0.642

Gnomad4 FIN exome AF: 0.685

Gnomad4 NFE exome AF: 0.795

Gnomad4 OTH exome AF: 0.709

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

Gnomad4 AFR AF: 0.394

Gnomad4 AMR AF: 0.587

Gnomad4 ASJ AF: 0.732

Gnomad4 EAS AF: 0.236

Gnomad4 SAS AF: 0.616

Gnomad4 FIN AF: 0.670

Gnomad4 NFE AF: 0.793

Gnomad4 OTH AF: 0.654

Alfa AF: 0.755 Hom.: 74319

Bravo AF: 0.606

Asia WGS AF: 0.485 AC: 1690 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Posterior polymorphous corneal dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Corneal dystrophy, Fuchs endothelial, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.35
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs274754; hg19: chr1-36565617;