21-45488441-T-C

Variant names:

Variant summary

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

The NM_001379500.1(COL18A1):c.1920T>C(p.Leu640Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,613,522 control chromosomes in the GnomAD database, including 76,375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L640L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.32 ( 7874 hom., cov: 32)

Exomes 𝑓: 0.30 ( 68501 hom. )

Consequence

COL18A1
NM_001379500.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.0120

Publications

44 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=-0.83).

BP6

Variant 21-45488441-T-C is Benign according to our data. Variant chr21-45488441-T-C is described in ClinVar as [Benign]. Clinvar id is 261895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.012 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.1920T>C	p.Leu640Leu	synonymous_variant	Exon 18 of 42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 link	c.3165T>C	p.Leu1055Leu	synonymous_variant	Exon 17 of 41		NP_569711.2	P39060
COL18A1	NM_030582.4 link	c.2460T>C	p.Leu820Leu	synonymous_variant	Exon 17 of 41		NP_085059.2	P39060D3DSM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL18A1	ENST00000651438.1 link	c.1920T>C	p.Leu640Leu	synonymous_variant	Exon 18 of 42		NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10 link	c.2460T>C	p.Leu820Leu	synonymous_variant	Exon 17 of 41	1		ENSP00000347665.5	P39060-1
COL18A1	ENST00000359759.8 link	c.3165T>C	p.Leu1055Leu	synonymous_variant	Exon 17 of 41	5		ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.320

AC:

48675

AN:

151910

Hom.:

7863

Cov.:

show subpopulations

Gnomad AFR

AF:

0.366

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.292

Gnomad ASJ

AF:

0.320

Gnomad EAS

AF:

0.243

Gnomad SAS

AF:

0.334

Gnomad FIN

AF:

0.356

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.300

Gnomad OTH

AF:

0.324

GnomAD2 exomes

AF:

0.303

AC:

75475

AN:

249126

AF XY:

0.304

show subpopulations

Gnomad AFR exome

AF:

0.373

Gnomad AMR exome

AF:

0.254

Gnomad ASJ exome

AF:

0.333

Gnomad EAS exome

AF:

0.241

Gnomad FIN exome

AF:

0.343

Gnomad NFE exome

AF:

0.303

Gnomad OTH exome

AF:

0.295

GnomAD4 exome

AF:

0.305

AC:

445715

AN:

1461494

Hom.:

68501

Cov.:

AF XY:

0.305

AC XY:

221950

AN XY:

727022

show subpopulations

African (AFR)

AF:

0.374

AC:

12526

AN:

33480

American (AMR)

AF:

0.261

AC:

11685

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.337

AC:

8817

AN:

26134

East Asian (EAS)

AF:

0.257

AC:

10216

AN:

39696

South Asian (SAS)

AF:

0.322

AC:

27813

AN:

86258

European-Finnish (FIN)

AF:

0.329

AC:

17477

AN:

53144

Middle Eastern (MID)

AF:

0.321

AC:

1852

AN:

5768

European-Non Finnish (NFE)

AF:

0.303

AC:

337438

AN:

1111918

Other (OTH)

AF:

0.296

AC:

17891

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

19152

38303

57455

76606

95758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.320

AC:

48714

AN:

152028

Hom.:

7874

Cov.:

AF XY:

0.324

AC XY:

24095

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.366

AC:

15183

AN:

41476

American (AMR)

AF:

0.292

AC:

4461

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.320

AC:

1108

AN:

3466

East Asian (EAS)

AF:

0.244

AC:

1252

AN:

5134

South Asian (SAS)

AF:

0.334

AC:

1610

AN:

4818

European-Finnish (FIN)

AF:

0.356

AC:

3759

AN:

10572

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.300

AC:

20385

AN:

67960

Other (OTH)

AF:

0.322

AC:

679

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1696

3392

5089

6785

8481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.305

Hom.:

27466

Bravo

AF:

0.317

Asia WGS

AF:

0.290

AC:

1011

AN:

3478

EpiCase

AF:

0.305

EpiControl

AF:

0.308

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Knobloch syndrome

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

4.4

(source)

DANN

Benign

0.50

PhyloP100

-0.012

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.4

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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21-45488441-T-C

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