21-45480419-C-G

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.1399-48C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0761 in 1,613,576 control chromosomes in the GnomAD database, including 6,177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1293 hom., cov: 33)

Exomes 𝑓: 0.073 ( 4884 hom. )

Consequence

COL18A1
NM_001379500.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.00

Publications

6 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=-0.89).

BP6

Variant 21-45480419-C-G is Benign according to our data. Variant chr21-45480419-C-G is described in ClinVar as Benign. ClinVar VariationId is 261891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.1399-48C>G	intron_variant	Intron 11 of 41	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 link	c.2644-48C>G	intron_variant	Intron 10 of 40		NP_569711.2	P39060
COL18A1	NM_030582.4 link	c.1939-48C>G	intron_variant	Intron 10 of 40		NP_085059.2	P39060D3DSM5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL18A1	ENST00000651438.1 link	c.1399-48C>G	intron_variant	Intron 11 of 41		NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10 link	c.1939-48C>G	intron_variant	Intron 10 of 40	1		ENSP00000347665.5	P39060-1
COL18A1	ENST00000359759.8 link	c.2644-48C>G	intron_variant	Intron 10 of 40	5		ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.109

AC:

16543

AN:

152068

Hom.:

1291

Cov.:

show subpopulations

Gnomad AFR

AF:

0.220

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0757

Gnomad ASJ

AF:

0.0533

Gnomad EAS

AF:

0.102

Gnomad SAS

AF:

0.136

Gnomad FIN

AF:

0.0184

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0659

Gnomad OTH

AF:

0.0951

GnomAD2 exomes

AF:

0.0785

AC:

19499

AN:

248366

AF XY:

0.0788

show subpopulations

Gnomad AFR exome

AF:

0.224

Gnomad AMR exome

AF:

0.0513

Gnomad ASJ exome

AF:

0.0513

Gnomad EAS exome

AF:

0.0962

Gnomad FIN exome

AF:

0.0219

Gnomad NFE exome

AF:

0.0651

Gnomad OTH exome

AF:

0.0715

GnomAD4 exome

AF:

0.0727

AC:

106231

AN:

1461390

Hom.:

4884

Cov.:

AF XY:

0.0737

AC XY:

53598

AN XY:

726990

show subpopulations

African (AFR)

AF:

0.232

AC:

7751

AN:

33478

American (AMR)

AF:

0.0558

AC:

2496

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0507

AC:

1324

AN:

26130

East Asian (EAS)

AF:

0.140

AC:

5541

AN:

39698

South Asian (SAS)

AF:

0.122

AC:

10556

AN:

86254

European-Finnish (FIN)

AF:

0.0222

AC:

1180

AN:

53042

Middle Eastern (MID)

AF:

0.0960

AC:

554

AN:

5768

European-Non Finnish (NFE)

AF:

0.0646

AC:

71787

AN:

1111922

Other (OTH)

AF:

0.0835

AC:

5042

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

6090

12181

18271

24362

30452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2842

5684

8526

11368

14210

<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:

0.109

AC:

16556

AN:

152186

Hom.:

1293

Cov.:

AF XY:

0.106

AC XY:

7851

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.220

AC:

9106

AN:

41480

American (AMR)

AF:

0.0753

AC:

1153

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0533

AC:

185

AN:

3472

East Asian (EAS)

AF:

0.102

AC:

527

AN:

5164

South Asian (SAS)

AF:

0.136

AC:

656

AN:

4810

European-Finnish (FIN)

AF:

0.0184

AC:

196

AN:

10626

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0659

AC:

4482

AN:

68012

Other (OTH)

AF:

0.0941

AC:

199

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

718

1436

2153

2871

3589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

182

364

546

728

910

<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:

0.0409

Hom.:

Bravo

AF:

0.117

Asia WGS

AF:

0.116

AC:

403

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 11, 2021

GeneDx

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.29

(source)

DANN

Benign

0.79

PhyloP100

-3.0

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