rs2236451

Variant names:

• chr21-45456169-A-G
• rs2236451
• ENST00000355480.10:c.639A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_130444.3(COL18A1):​c.639A>G​(p.Pro213Pro) 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 NM_130444.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.00
• Publications: 33 publications found

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]

COL18A1 Gene-Disease associations (from GenCC):

• Knobloch syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• Knobloch syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
• hereditary glaucoma, primary closed-angle

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 261919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130444.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.107-12073A>G		intron	N/A	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.639A>G	p.Pro213Pro	synonymous	Exon 1 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.639A>G	p.Pro213Pro	synonymous	Exon 1 of 41	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000355480.10	TSL:1	c.639A>G	p.Pro213Pro	synonymous	Exon 1 of 41	ENSP00000347665.5	P39060-1
	COL18A1	ENST00000651438.1	MANE Select	c.107-12073A>G		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000359759.8	TSL:5	c.639A>G	p.Pro213Pro	synonymous	Exon 1 of 41	ENSP00000352798.4	P39060-3

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

GnomAD2 exomes AF: 0.335 AC: 78967 AN: 236058 AF XY: 0.334

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 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

African (AFR) AF: 0.545 AC: 17995 AN: 33036

American (AMR) AF: 0.270 AC: 11727 AN: 43466

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 10374 AN: 24682

East Asian (EAS) AF: 0.286 AC: 11244 AN: 39334

South Asian (SAS) AF: 0.296 AC: 24763 AN: 83540

European-Finnish (FIN) AF: 0.317 AC: 16433 AN: 51902

Middle Eastern (MID) AF: 0.401 AC: 2265 AN: 5652

European-Non Finnish (NFE) AF: 0.332 AC: 364145 AN: 1097560

Other (OTH) AF: 0.349 AC: 20661 AN: 59238

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

African (AFR) AF: 0.533 AC: 22097 AN: 41466

American (AMR) AF: 0.317 AC: 4844 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1479 AN: 3470

East Asian (EAS) AF: 0.335 AC: 1713 AN: 5116

South Asian (SAS) AF: 0.302 AC: 1452 AN: 4810

European-Finnish (FIN) AF: 0.328 AC: 3460 AN: 10560

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.331 AC: 22511 AN: 67912

Other (OTH) AF: 0.390 AC: 822 AN: 2110

Alfa AF: 0.349 Hom.: 29927

Bravo AF: 0.392

Asia WGS AF: 0.327 AC: 1141 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary glaucoma, primary closed-angle (1)
-	-	1	Knobloch syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.15
DANN	Benign	0.30
PhyloP100		-2.0
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: rs2236451; hg19: chr21-46876083; COSMIC: COSV62698519;