21-45455650-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_130444.3(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
NM_130444.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0690

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 518320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45455650-T-C is described in Lovd as [Benign].

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

GnomAD3 exomes

AF:

0.970

AC:

242021

AN:

249428

Hom.:

117452

AF XY:

0.970

AC XY:

131337

AN XY:

135368

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 SAS exome

AF:

0.991

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

Gnomad4 AFR exome

AF:

0.994

Gnomad4 AMR exome

AF:

0.983

Gnomad4 ASJ exome

AF:

0.963

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.990

Gnomad4 FIN exome

AF:

0.956

Gnomad4 NFE exome

AF:

0.955

Gnomad4 OTH exome

AF:

0.964

GnomAD4 genome

AF:

0.971

AC:

147821

AN:

152312

Hom.:

71767

Cov.:

AF XY:

0.971

AC XY:

72321

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.992

Gnomad4 AMR

AF:

0.978

Gnomad4 ASJ

AF:

0.967

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.990

Gnomad4 FIN

AF:

0.952

Gnomad4 NFE

AF:

0.955

Gnomad4 OTH

AF:

0.976

Alfa

AF:

0.961

Hom.:

137006

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Knobloch syndrome

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

Jan 23, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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

DANN

Benign

0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over