rs12482088

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001379500.1(COL18A1):c.1674+34A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,565,148 control chromosomes in the GnomAD database, including 42,774 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 3961 hom., cov: 34)

Exomes 𝑓: 0.23 ( 38813 hom. )

Consequence

COL18A1
NM_001379500.1 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0730

Publications

16 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BP6

Variant 21-45482059-A-C is Benign according to our data. Variant chr21-45482059-A-C is described in ClinVar as Benign. ClinVar VariationId is 261892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.1674+34A>C	intron_variant	Intron 14 of 41	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 link	c.2919+34A>C	intron_variant	Intron 13 of 40		NP_569711.2	P39060
COL18A1	NM_030582.4 link	c.2214+34A>C	intron_variant	Intron 13 of 40		NP_085059.2	P39060D3DSM5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL18A1	ENST00000651438.1 link	c.1674+34A>C	intron_variant	Intron 14 of 41		NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10 link	c.2214+34A>C	intron_variant	Intron 13 of 40	1		ENSP00000347665.5	P39060-1
COL18A1	ENST00000359759.8 link	c.2919+34A>C	intron_variant	Intron 13 of 40	5		ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.229

AC:

34803

AN:

152110

Hom.:

3958

Cov.:

show subpopulations

Gnomad AFR

AF:

0.231

Gnomad AMI

AF:

0.0987

Gnomad AMR

AF:

0.239

Gnomad ASJ

AF:

0.261

Gnomad EAS

AF:

0.140

Gnomad SAS

AF:

0.185

Gnomad FIN

AF:

0.213

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.237

Gnomad OTH

AF:

0.244

GnomAD2 exomes

AF:

0.220

AC:

51289

AN:

233228

AF XY:

0.219

show subpopulations

Gnomad AFR exome

AF:

0.232

Gnomad AMR exome

AF:

0.224

Gnomad ASJ exome

AF:

0.262

Gnomad EAS exome

AF:

0.140

Gnomad FIN exome

AF:

0.215

Gnomad NFE exome

AF:

0.238

Gnomad OTH exome

AF:

0.227

GnomAD4 exome

AF:

0.234

AC:

330593

AN:

1412920

Hom.:

38813

Cov.:

AF XY:

0.232

AC XY:

163775

AN XY:

704918

show subpopulations

African (AFR)

AF:

0.233

AC:

7595

AN:

32540

American (AMR)

AF:

0.229

AC:

10043

AN:

43904

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

6951

AN:

25734

East Asian (EAS)

AF:

0.123

AC:

4819

AN:

39304

South Asian (SAS)

AF:

0.183

AC:

15449

AN:

84566

European-Finnish (FIN)

AF:

0.208

AC:

10956

AN:

52776

Middle Eastern (MID)

AF:

0.256

AC:

1452

AN:

5668

European-Non Finnish (NFE)

AF:

0.243

AC:

260078

AN:

1069820

Other (OTH)

AF:

0.226

AC:

13250

AN:

58608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

12224

24449

36673

48898

61122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8778

17556

26334

35112

43890

<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:

0.229

AC:

34823

AN:

152228

Hom.:

3961

Cov.:

AF XY:

0.227

AC XY:

16923

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.231

AC:

9603

AN:

41550

American (AMR)

AF:

0.239

AC:

3656

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.261

AC:

904

AN:

3470

East Asian (EAS)

AF:

0.140

AC:

724

AN:

5168

South Asian (SAS)

AF:

0.186

AC:

895

AN:

4824

European-Finnish (FIN)

AF:

0.213

AC:

2261

AN:

10612

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.237

AC:

16101

AN:

67980

Other (OTH)

AF:

0.242

AC:

511

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1403

2806

4209

5612

7015

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

374

748

1122

1496

1870

<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:

0.235

Hom.:

1253

Bravo

AF:

0.232

Asia WGS

AF:

0.179

AC:

623

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

May 10, 2021

GeneDx

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

-0.97

CADD

Benign

6.2

(source)

DANN

Benign

0.26

PhyloP100

0.073

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