NM_001379500.1:c.837C>G

Variant names:

• chr21-45476389-C-G
• rs2230687
• NM_001379500.1:c.837C>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_001379500.1(COL18A1):​c.837C>G​(p.Pro279Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,613,466 control chromosomes in the GnomAD database, including 17,226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P279P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.20 (4245 hom., cov: 34)
  • Exomes 𝑓: 0.12 (12981 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.84
• Publications: 20 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=-0.8).
• BP6: Variant 21-45476389-C-G is Benign according to our data. Variant chr21-45476389-C-G is described in ClinVar as Benign. ClinVar VariationId is 261886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.84 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379500.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.837C>G	p.Pro279Pro	synonymous	Exon 6 of 42	NP_001366429.1
	COL18A1	NM_130444.3		c.2082C>G	p.Pro694Pro	synonymous	Exon 5 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.1377C>G	p.Pro459Pro	synonymous	Exon 5 of 41	NP_085059.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.837C>G	p.Pro279Pro	synonymous	Exon 6 of 42	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.1377C>G	p.Pro459Pro	synonymous	Exon 5 of 41	ENSP00000347665.5
	COL18A1	ENST00000359759.8	TSL:5	c.2082C>G	p.Pro694Pro	synonymous	Exon 5 of 41	ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29722 AN: 151944 Hom.: 4232 Cov.: 34

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.0972

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.147 AC: 36327 AN: 247204 AF XY: 0.143

Gnomad AFR exome AF: 0.396

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.301

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.0948

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.117 AC: 170845 AN: 1461402 Hom.: 12981 Cov.: 33 AF XY: 0.117 AC XY: 85337 AN XY: 726982

African (AFR) AF: 0.412 AC: 13771 AN: 33462

American (AMR) AF: 0.134 AC: 6002 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3805 AN: 26128

East Asian (EAS) AF: 0.321 AC: 12725 AN: 39652

South Asian (SAS) AF: 0.164 AC: 14107 AN: 86212

European-Finnish (FIN) AF: 0.115 AC: 6115 AN: 53352

Middle Eastern (MID) AF: 0.151 AC: 872 AN: 5768

European-Non Finnish (NFE) AF: 0.0942 AC: 104710 AN: 1111808

Other (OTH) AF: 0.145 AC: 8738 AN: 60370

GnomAD4 genome AF: 0.196 AC: 29776 AN: 152064 Hom.: 4245 Cov.: 34 AF XY: 0.197 AC XY: 14632 AN XY: 74352

African (AFR) AF: 0.393 AC: 16260 AN: 41388

American (AMR) AF: 0.140 AC: 2144 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 560 AN: 3472

East Asian (EAS) AF: 0.301 AC: 1552 AN: 5158

South Asian (SAS) AF: 0.169 AC: 815 AN: 4816

European-Finnish (FIN) AF: 0.120 AC: 1273 AN: 10616

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.0972 AC: 6612 AN: 68008

Other (OTH) AF: 0.178 AC: 374 AN: 2106

Alfa AF: 0.0772 Hom.: 141

Bravo AF: 0.207

EpiCase AF: 0.0977

EpiControl AF: 0.0959

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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 12, 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.012
DANN	Benign	0.39
PhyloP100		-4.8
Mutation Taster		=99/1	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: rs2230687; hg19: chr21-46896303; COSMIC: COSV62702076; COSMIC: COSV62702076;