rs2236451

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000355480.10(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
ENST00000355480.10 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.00

Publications

33 publications found

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 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

COL18A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.107-12073A>G		intron_variant	Intron 2 of 41	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 link	c.639A>G	p.Pro213Pro	synonymous_variant	Exon 1 of 41		NP_569711.2	P39060
COL18A1	NM_030582.4 link	c.639A>G	p.Pro213Pro	synonymous_variant	Exon 1 of 41		NP_085059.2	P39060D3DSM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL18A1	ENST00000355480.10 link	c.639A>G	p.Pro213Pro	synonymous_variant	Exon 1 of 41	1		ENSP00000347665.5	P39060-1
COL18A1	ENST00000651438.1 link	c.107-12073A>G		intron_variant	Intron 2 of 41		NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1	ENST00000359759.8 link	c.639A>G	p.Pro213Pro	synonymous_variant	Exon 1 of 41	5		ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.387

AC:

58677

AN:

151814

Hom.:

12038

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.332

AC XY:

236777

AN XY:

712200

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

19899

39798

59696

79595

99494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12022

24044

36066

48088

60110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.387

AC:

58724

AN:

151936

Hom.:

12049

Cov.:

AF XY:

0.385

AC XY:

28620

AN XY:

74246

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1857

3714

5570

7427

9284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

556

1112

1668

2224

2780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.349

Hom.:

29927

Bravo

AF:

0.392

Asia WGS

AF:

0.327

AC:

1141

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

- -

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

- -

Knobloch syndrome

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

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.15

(source)

DANN

Benign

0.30

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over