21-45489512-G-A

Variant names:

• chr21-45489512-G-A
• rs61731167
• NM_001379500.1:c.1950G>A

Variant summary

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

The NM_001379500.1(COL18A1):​c.1950G>A​(p.Pro650Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0645 in 1,599,814 control chromosomes in the GnomAD database, including 3,930 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (348 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3582 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.99
• Publications: 8 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• 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=-0.92).
• BP6: Variant 21-45489512-G-A is Benign according to our data. Variant chr21-45489512-G-A is described in ClinVar as Benign. ClinVar VariationId is 261896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.1950G>A	p.Pro650Pro	synonymous_variant	Exon 19 of 42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.3195G>A	p.Pro1065Pro	synonymous_variant	Exon 18 of 41		NP_569711.2
COL18A1	NM_030582.4	c.2490G>A	p.Pro830Pro	synonymous_variant	Exon 18 of 41		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.1950G>A	p.Pro650Pro	synonymous_variant	Exon 19 of 42		NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000355480.10	c.2490G>A	p.Pro830Pro	synonymous_variant	Exon 18 of 41	1		ENSP00000347665.5
COL18A1	ENST00000359759.8	c.3195G>A	p.Pro1065Pro	synonymous_variant	Exon 18 of 41	5		ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.0582 AC: 8856 AN: 152116 Hom.: 349 Cov.: 32

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0394

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.00753

Gnomad SAS AF: 0.0985

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0664

Gnomad OTH AF: 0.0522

GnomAD2 exomes AF: 0.0653 AC: 14887 AN: 227988 AF XY: 0.0687

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.0257

Gnomad ASJ exome AF: 0.0680

Gnomad EAS exome AF: 0.0106

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.0676

Gnomad OTH exome AF: 0.0618

GnomAD4 exome AF: 0.0652 AC: 94316 AN: 1447580 Hom.: 3582 Cov.: 30 AF XY: 0.0666 AC XY: 47913 AN XY: 719110

African (AFR) AF: 0.0277 AC: 921 AN: 33190

American (AMR) AF: 0.0261 AC: 1135 AN: 43494

Ashkenazi Jewish (ASJ) AF: 0.0656 AC: 1682 AN: 25656

East Asian (EAS) AF: 0.00519 AC: 204 AN: 39344

South Asian (SAS) AF: 0.102 AC: 8590 AN: 84410

European-Finnish (FIN) AF: 0.135 AC: 6945 AN: 51510

Middle Eastern (MID) AF: 0.0632 AC: 359 AN: 5684

European-Non Finnish (NFE) AF: 0.0644 AC: 71077 AN: 1104518

Other (OTH) AF: 0.0569 AC: 3403 AN: 59774

GnomAD4 genome AF: 0.0583 AC: 8873 AN: 152234 Hom.: 348 Cov.: 32 AF XY: 0.0632 AC XY: 4701 AN XY: 74420

African (AFR) AF: 0.0274 AC: 1139 AN: 41548

American (AMR) AF: 0.0393 AC: 602 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0599 AC: 208 AN: 3470

East Asian (EAS) AF: 0.00774 AC: 40 AN: 5168

South Asian (SAS) AF: 0.0988 AC: 477 AN: 4830

European-Finnish (FIN) AF: 0.158 AC: 1673 AN: 10608

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0664 AC: 4516 AN: 67986

Other (OTH) AF: 0.0521 AC: 110 AN: 2110

Alfa AF: 0.0598 Hom.: 114

Bravo AF: 0.0472

Asia WGS AF: 0.0440 AC: 156 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Knobloch syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.12
DANN	Benign	0.66
PhyloP100		-6.0
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
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: rs61731167; hg19: chr21-46909426; COSMIC: COSV107421593; COSMIC: COSV107421593;