21-45455650-T-C

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.120T>C(p.His40His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.962 in 1,613,912 control chromosomes in the GnomAD database, including 746,811 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.97 ( 71767 hom., cov: 34)

Exomes 𝑓: 0.96 ( 675044 hom. )

Consequence

COL18A1
ENST00000355480.10 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0690

Publications

19 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=-0.98).

BP6

Variant 21-45455650-T-C is Benign according to our data. Variant chr21-45455650-T-C is described in ClinVar as Benign. ClinVar VariationId is 518320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.069 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.984 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.107-12592T>C		intron_variant	Intron 2 of 41	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 link	c.120T>C	p.His40His	synonymous_variant	Exon 1 of 41		NP_569711.2	P39060
COL18A1	NM_030582.4 link	c.120T>C	p.His40His	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.120T>C	p.His40His	synonymous_variant	Exon 1 of 41	1		ENSP00000347665.5	P39060-1
COL18A1	ENST00000651438.1 link	c.107-12592T>C		intron_variant	Intron 2 of 41		NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1	ENST00000359759.8 link	c.120T>C	p.His40His	synonymous_variant	Exon 1 of 41	5		ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.970

AC:

147700

AN:

152194

Hom.:

71705

Cov.:

show subpopulations

Gnomad AFR

AF:

0.992

Gnomad AMI

AF:

0.992

Gnomad AMR

AF:

0.978

Gnomad ASJ

AF:

0.967

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.990

Gnomad FIN

AF:

0.952

Gnomad MID

AF:

0.978

Gnomad NFE

AF:

0.955

Gnomad OTH

AF:

0.975

GnomAD2 exomes

AF:

0.970

AC:

242021

AN:

249428

AF XY:

0.970

show subpopulations

Gnomad AFR exome

AF:

0.993

Gnomad AMR exome

AF:

0.984

Gnomad ASJ exome

AF:

0.963

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.956

Gnomad NFE exome

AF:

0.956

Gnomad OTH exome

AF:

0.965

GnomAD4 exome

AF:

0.961

AC:

1404607

AN:

1461600

Hom.:

675044

Cov.:

AF XY:

0.962

AC XY:

699397

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.994

AC:

33267

AN:

33480

American (AMR)

AF:

0.983

AC:

43972

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.963

AC:

25178

AN:

26134

East Asian (EAS)

AF:

1.00

AC:

39697

AN:

39700

South Asian (SAS)

AF:

0.990

AC:

85369

AN:

86258

European-Finnish (FIN)

AF:

0.956

AC:

50802

AN:

53150

Middle Eastern (MID)

AF:

0.982

AC:

5666

AN:

5768

European-Non Finnish (NFE)

AF:

0.955

AC:

1062435

AN:

1111996

Other (OTH)

AF:

0.964

AC:

58221

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

3722

7444

11167

14889

18611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21630

43260

64890

86520

108150

<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:

0.971

AC:

147821

AN:

152312

Hom.:

71767

Cov.:

AF XY:

0.971

AC XY:

72321

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.992

AC:

41238

AN:

41574

American (AMR)

AF:

0.978

AC:

14977

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.967

AC:

3356

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5170

AN:

5170

South Asian (SAS)

AF:

0.990

AC:

4782

AN:

4828

European-Finnish (FIN)

AF:

0.952

AC:

10115

AN:

10624

Middle Eastern (MID)

AF:

0.980

AC:

288

AN:

294

European-Non Finnish (NFE)

AF:

0.955

AC:

64925

AN:

68014

Other (OTH)

AF:

0.976

AC:

2065

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

242

483

725

966

1208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.964

Hom.:

223080

Bravo

AF:

0.974

Asia WGS

AF:

0.995

AC:

3460

AN:

3478

EpiCase

AF:

0.961

EpiControl

AF:

0.961

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 10, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Knobloch syndrome

Benign:3

Jan 23, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

-0.98

CADD

Benign

6.3

(source)

DANN

Benign

0.41

PhyloP100

-0.069

PromoterAI

0.049

Neutral

(source)

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