21-45490296-G-A

Variant names:

• chr21-45490296-G-A
• rs62000962
• NM_001379500.1:c.1981G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379500.1(COL18A1):​c.1981G>A​(p.Val661Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,585,750 control chromosomes in the GnomAD database, including 12,184 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V661V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.13 (1323 hom., cov: 24)
  • Exomes 𝑓: 0.12 (10861 hom.)
• Consequence: COL18A1 NM_001379500.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.29
• Publications: 21 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025745034).
• BP6: Variant 21-45490296-G-A is Benign according to our data. Variant chr21-45490296-G-A is described in ClinVar as Benign. ClinVar VariationId is 261897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.1981G>A	p.Val661Ile	missense_variant	Exon 20 of 42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.3226G>A	p.Val1076Ile	missense_variant	Exon 19 of 41		NP_569711.2
COL18A1	NM_030582.4	c.2521G>A	p.Val841Ile	missense_variant	Exon 19 of 41		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.1981G>A	p.Val661Ile	missense_variant	Exon 20 of 42		NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000355480.10	c.2521G>A	p.Val841Ile	missense_variant	Exon 19 of 41	1		ENSP00000347665.5
COL18A1	ENST00000359759.8	c.3226G>A	p.Val1076Ile	missense_variant	Exon 19 of 41	5		ENSP00000352798.4
COL18A1	ENST00000342220.9	c.22G>A	p.Val8Ile	missense_variant	Exon 1 of 23	2		ENSP00000339118.5

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19249 AN: 150530 Hom.: 1321 Cov.: 24

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.0959

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.0980

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.116 AC: 23942 AN: 206612 AF XY: 0.119

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.0706

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.0179

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.120 AC: 171574 AN: 1435110 Hom.: 10861 Cov.: 32 AF XY: 0.121 AC XY: 85934 AN XY: 711530

African (AFR) AF: 0.156 AC: 5178 AN: 33166

American (AMR) AF: 0.0740 AC: 3027 AN: 40906

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2724 AN: 25588

East Asian (EAS) AF: 0.0144 AC: 557 AN: 38734

South Asian (SAS) AF: 0.152 AC: 12571 AN: 82484

European-Finnish (FIN) AF: 0.154 AC: 7715 AN: 50212

Middle Eastern (MID) AF: 0.135 AC: 761 AN: 5636

European-Non Finnish (NFE) AF: 0.120 AC: 132167 AN: 1099008

Other (OTH) AF: 0.116 AC: 6874 AN: 59376

GnomAD4 genome AF: 0.128 AC: 19272 AN: 150640 Hom.: 1323 Cov.: 24 AF XY: 0.129 AC XY: 9462 AN XY: 73512

African (AFR) AF: 0.150 AC: 6157 AN: 40948

American (AMR) AF: 0.0954 AC: 1453 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 366 AN: 3466

East Asian (EAS) AF: 0.0153 AC: 76 AN: 4972

South Asian (SAS) AF: 0.147 AC: 700 AN: 4746

European-Finnish (FIN) AF: 0.172 AC: 1793 AN: 10438

Middle Eastern (MID) AF: 0.0909 AC: 26 AN: 286

European-Non Finnish (NFE) AF: 0.123 AC: 8335 AN: 67556

Other (OTH) AF: 0.115 AC: 242 AN: 2098

Alfa AF: 0.121 Hom.: 1850

Bravo AF: 0.124

TwinsUK AF: 0.115 AC: 426

ALSPAC AF: 0.115 AC: 442

ESP6500AA AF: 0.149 AC: 564

ESP6500EA AF: 0.112 AC: 918

ExAC AF: 0.105 AC: 12455

Asia WGS AF: 0.0840 AC: 293 AN: 3476

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

- -

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

- -

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
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.42
DANN	Benign	0.70
DEOGEN2	Benign	0.23	.;.;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.079	N
LIST_S2	Uncertain	0.87	D;D;D;D
MetaRNN	Benign	0.0026	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.050	.;.;N;.
PhyloP100		-1.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.45	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.42	T;T;T;T
Sift4G	Benign	0.43	T;T;T;T
Polyphen		0.016	B;B;B;.
Vest4		0.076
MPC		0.063
ClinPred		0.00058	T
GERP RS		-2.5
PromoterAI		-0.00020	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.011
gMVP		0.069
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: rs62000962; hg19: chr21-46910210; COSMIC: COSV60589683; COSMIC: COSV60589683;