chr21-45491274-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001379500.1(COL18A1):c.2117C>G(p.Pro706Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0788 in 1,612,096 control chromosomes in the GnomAD database, including 5,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.071 ( 494 hom., cov: 32)

Exomes 𝑓: 0.080 ( 5149 hom. )

Consequence

COL18A1
NM_001379500.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.57

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020926893).

BP6

Variant 21-45491274-C-G is Benign according to our data. Variant chr21-45491274-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 261898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45491274-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.2117C>G	p.Pro706Arg	missense_variant	Exon 22 of 42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 link	c.3362C>G	p.Pro1121Arg	missense_variant	Exon 21 of 41		NP_569711.2	P39060
COL18A1	NM_030582.4 link	c.2657C>G	p.Pro886Arg	missense_variant	Exon 21 of 41		NP_085059.2	P39060D3DSM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL18A1	ENST00000651438.1 link	c.2117C>G	p.Pro706Arg	missense_variant	Exon 22 of 42		NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10 link	c.2657C>G	p.Pro886Arg	missense_variant	Exon 21 of 41	1		ENSP00000347665.5	P39060-1
COL18A1	ENST00000359759.8 link	c.3362C>G	p.Pro1121Arg	missense_variant	Exon 21 of 41	5		ENSP00000352798.4	P39060-3
COL18A1	ENST00000342220.9 link	c.158C>G	p.Pro53Arg	missense_variant	Exon 3 of 23	2		ENSP00000339118.5	H7BXV5

Frequencies

GnomAD3 genomes

AF:

0.0708

AC:

10765

AN:

152120

Hom.:

496

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0325

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.0428

Gnomad ASJ

AF:

0.0637

Gnomad EAS

AF:

0.0711

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.170

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0816

Gnomad OTH

AF:

0.0599

GnomAD3 exomes

AF:

0.0830

AC:

20339

AN:

245174

Hom.:

1058

AF XY:

0.0871

AC XY:

11678

AN XY:

134142

show subpopulations

Gnomad AFR exome

AF:

0.0336

Gnomad AMR exome

AF:

0.0292

Gnomad ASJ exome

AF:

0.0726

Gnomad EAS exome

AF:

0.0766

Gnomad SAS exome

AF:

0.117

Gnomad FIN exome

AF:

0.157

Gnomad NFE exome

AF:

0.0847

Gnomad OTH exome

AF:

0.0772

GnomAD4 exome

AF:

0.0796

AC:

116225

AN:

1459858

Hom.:

5149

Cov.:

AF XY:

0.0812

AC XY:

58956

AN XY:

726214

show subpopulations

Gnomad4 AFR exome

AF:

0.0340

Gnomad4 AMR exome

AF:

0.0298

Gnomad4 ASJ exome

AF:

0.0706

Gnomad4 EAS exome

AF:

0.0500

Gnomad4 SAS exome

AF:

0.119

Gnomad4 FIN exome

AF:

0.146

Gnomad4 NFE exome

AF:

0.0786

Gnomad4 OTH exome

AF:

0.0705

GnomAD4 genome

AF:

0.0707

AC:

10769

AN:

152238

Hom.:

494

Cov.:

AF XY:

0.0756

AC XY:

5626

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0326

Gnomad4 AMR

AF:

0.0427

Gnomad4 ASJ

AF:

0.0637

Gnomad4 EAS

AF:

0.0710

Gnomad4 SAS

AF:

0.119

Gnomad4 FIN

AF:

0.170

Gnomad4 NFE

AF:

0.0816

Gnomad4 OTH

AF:

0.0598

Alfa

AF:

0.0627

Hom.:

131

Bravo

AF:

0.0589

ESP6500AA

AF:

0.0326

AC:

125

ESP6500EA

AF:

0.0726

AC:

594

ExAC

AF:

0.0833

AC:

9991

Asia WGS

AF:

0.0880

AC:

308

AN:

3478

EpiCase

AF:

0.0766

EpiControl

AF:

0.0792

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2018

Athena Diagnostics

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Knobloch syndrome

Benign:3

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. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary glaucoma, primary closed-angle

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

.;.;D;D

Eigen

Benign

0.18

Eigen_PC

Benign

0.051

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.81

T;T;T;T

MetaRNN

Benign

0.0021

T;T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Uncertain

2.3

.;.;M;.

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-5.7

D;D;D;D

REVEL

Uncertain

0.43

Sift

Benign

0.094

T;T;T;D

Sift4G

Benign

0.17

T;T;T;T

Polyphen

1.0

D;D;D;.

Vest4

0.33

MPC

0.42

ClinPred

0.033

GERP RS

3.9

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.9

Varity_R

0.28

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over