chr1-36100398-A-G

Variant names:

• chr1-36100398-A-G
• rs4652900
• NM_005202.4:c.-16-140T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005202.4(COL8A2):​c.-16-140T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 798,448 control chromosomes in the GnomAD database, including 213,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.64 (33796 hom., cov: 31)
  • Exomes 𝑓: 0.73 (179743 hom.)
• Consequence: COL8A2 NM_005202.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.192
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-36100398-A-G is Benign according to our data. Variant chr1-36100398-A-G is described in ClinVar as Benign. ClinVar VariationId is 1234641.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL8A2	NM_005202.4	c.-16-140T>C		intron_variant	Intron 2 of 3	ENST00000397799.2	NP_005193.1
COL8A2	NM_001294347.2	c.-66-140T>C		intron_variant	Intron 2 of 3		NP_001281276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL8A2	ENST00000397799.2	c.-16-140T>C		intron_variant	Intron 2 of 3	5	NM_005202.4	ENSP00000380901.1
COL8A2	ENST00000481785.1	c.-206T>C		upstream_gene_variant		1		ENSP00000436433.1
COL8A2	ENST00000303143.9	c.-156T>C		upstream_gene_variant		2		ENSP00000305913.4

Frequencies

GnomAD3 genomes AF: 0.638 AC: 97015 AN: 151970 Hom.: 33794 Cov.: 31

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.594

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.660

GnomAD4 exome AF: 0.730 AC: 471530 AN: 646360 Hom.: 179743 AF XY: 0.729 AC XY: 245408 AN XY: 336508

African (AFR) AF: 0.391 AC: 6599 AN: 16882

American (AMR) AF: 0.549 AC: 15782 AN: 28770

Ashkenazi Jewish (ASJ) AF: 0.732 AC: 13215 AN: 18050

East Asian (EAS) AF: 0.235 AC: 7530 AN: 32094

South Asian (SAS) AF: 0.657 AC: 38234 AN: 58216

European-Finnish (FIN) AF: 0.723 AC: 23019 AN: 31820

Middle Eastern (MID) AF: 0.729 AC: 1990 AN: 2730

European-Non Finnish (NFE) AF: 0.805 AC: 341817 AN: 424822

Other (OTH) AF: 0.708 AC: 23344 AN: 32976

GnomAD4 genome AF: 0.638 AC: 97046 AN: 152088 Hom.: 33796 Cov.: 31 AF XY: 0.631 AC XY: 46883 AN XY: 74350

African (AFR) AF: 0.399 AC: 16563 AN: 41472

American (AMR) AF: 0.593 AC: 9053 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 2554 AN: 3472

East Asian (EAS) AF: 0.249 AC: 1287 AN: 5170

South Asian (SAS) AF: 0.633 AC: 3046 AN: 4812

European-Finnish (FIN) AF: 0.710 AC: 7510 AN: 10584

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.805 AC: 54738 AN: 67986

Other (OTH) AF: 0.660 AC: 1393 AN: 2112

Alfa AF: 0.693 Hom.: 16117

Bravo AF: 0.615

Asia WGS AF: 0.487 AC: 1697 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

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	-0.77
CADD	Benign	8.3
DANN	Benign	0.83
PhyloP100		-0.19
PromoterAI		0.013	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: rs4652900; hg19: chr1-36565999;