rs2236451

Positions:

• chr21-45456169-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000355480.10(COL18A1):​c.639A>G​(p.Pro213=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,590,346 control chromosomes in the GnomAD database, including 93,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12049 hom., cov: 33)
  • Exomes 𝑓: 0.33 (81529 hom.)
• Consequence: COL18A1 ENST00000355480.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.00

Genes affected

COL18A1 (HGNC:2195): (collagen type XVIII alpha 1 chain) This gene encodes the alpha chain of type XVIII collagen. This collagen is one of the multiplexins, extracellular matrix proteins that contain multiple triple-helix domains (collagenous domains) interrupted by non-collagenous domains. A long isoform of the protein has an N-terminal domain that is homologous to the extracellular part of frizzled receptors. Proteolytic processing at several endogenous cleavage sites in the C-terminal domain results in production of endostatin, a potent antiangiogenic protein that is able to inhibit angiogenesis and tumor growth. Mutations in this gene are associated with Knobloch syndrome. The main features of this syndrome involve retinal abnormalities, so type XVIII collagen may play an important role in retinal structure and in neural tube closure. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 21-45456169-A-G is Benign according to our data. Variant chr21-45456169-A-G is described in ClinVar as [Benign]. Clinvar id is 261919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45456169-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.107-12073A>G		intron_variant		ENST00000651438.1
COL18A1	NM_130444.3	c.639A>G	p.Pro213=	synonymous_variant	1/41
COL18A1	NM_030582.4	c.639A>G	p.Pro213=	synonymous_variant	1/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000355480.10	c.639A>G	p.Pro213=	synonymous_variant	1/41	1
COL18A1	ENST00000651438.1	c.107-12073A>G		intron_variant			NM_001379500.1
COL18A1	ENST00000359759.8	c.639A>G	p.Pro213=	synonymous_variant	1/41	5		P1

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58677 AN: 151814 Hom.: 12038 Cov.: 33

Gnomad AFR AF: 0.533

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.390

GnomAD3 exomes AF: 0.335 AC: 78967 AN: 236058 Hom.: 13821 AF XY: 0.334 AC XY: 42762 AN XY: 128100

Gnomad AFR exome AF: 0.539

Gnomad AMR exome AF: 0.266

Gnomad ASJ exome AF: 0.414

Gnomad EAS exome AF: 0.338

Gnomad SAS exome AF: 0.297

Gnomad FIN exome AF: 0.319

Gnomad NFE exome AF: 0.332

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.333 AC: 479607 AN: 1438410 Hom.: 81529 Cov.: 65 AF XY: 0.332 AC XY: 236777 AN XY: 712200

Gnomad4 AFR exome AF: 0.545

Gnomad4 AMR exome AF: 0.270

Gnomad4 ASJ exome AF: 0.420

Gnomad4 EAS exome AF: 0.286

Gnomad4 SAS exome AF: 0.296

Gnomad4 FIN exome AF: 0.317

Gnomad4 NFE exome AF: 0.332

Gnomad4 OTH exome AF: 0.349

GnomAD4 genome AF: 0.387 AC: 58724 AN: 151936 Hom.: 12049 Cov.: 33 AF XY: 0.385 AC XY: 28620 AN XY: 74246

Gnomad4 AFR AF: 0.533

Gnomad4 AMR AF: 0.317

Gnomad4 ASJ AF: 0.426

Gnomad4 EAS AF: 0.335

Gnomad4 SAS AF: 0.302

Gnomad4 FIN AF: 0.328

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.390

Alfa AF: 0.342 Hom.: 18547

Bravo AF: 0.392

Asia WGS AF: 0.327 AC: 1141 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Glaucoma, primary closed-angle Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Knobloch syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.15
DANN	Benign	0.30

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: rs2236451; hg19: chr21-46876083; COSMIC: COSV62698519;