chr21-45476389-C-G

Position:

chr21-45476389-C-G

Variant summary

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

The NM_001379500.1(COL18A1):c.837C>G(p.Pro279Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,613,466 control chromosomes in the GnomAD database, including 17,226 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. P279P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.20 ( 4245 hom., cov: 34)

Exomes 𝑓: 0.12 ( 12981 hom. )

Consequence

COL18A1
NM_001379500.1 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.84

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 21-45476389-C-G is Benign according to our data. Variant chr21-45476389-C-G is described in ClinVar as [Benign]. Clinvar id is 261886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45476389-C-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.84 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1 linkuse as main transcript	c.837C>G	p.Pro279Pro	synonymous_variant	6/42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 linkuse as main transcript	c.2082C>G	p.Pro694Pro	synonymous_variant	5/41		NP_569711.2	P39060
COL18A1	NM_030582.4 linkuse as main transcript	c.1377C>G	p.Pro459Pro	synonymous_variant	5/41		NP_085059.2	P39060D3DSM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL18A1	ENST00000651438.1 linkuse as main transcript	c.837C>G	p.Pro279Pro	synonymous_variant	6/42		NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10 linkuse as main transcript	c.1377C>G	p.Pro459Pro	synonymous_variant	5/41	1		ENSP00000347665.5	P39060-1
COL18A1	ENST00000359759.8 linkuse as main transcript	c.2082C>G	p.Pro694Pro	synonymous_variant	5/41	5		ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.196

AC:

29722

AN:

151944

Hom.:

4232

Cov.:

show subpopulations

Gnomad AFR

AF:

0.393

Gnomad AMI

AF:

0.150

Gnomad AMR

AF:

0.140

Gnomad ASJ

AF:

0.161

Gnomad EAS

AF:

0.301

Gnomad SAS

AF:

0.169

Gnomad FIN

AF:

0.120

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.0972

Gnomad OTH

AF:

0.179

GnomAD3 exomes

AF:

0.147

AC:

36327

AN:

247204

Hom.:

3474

AF XY:

0.143

AC XY:

19235

AN XY:

134568

show subpopulations

Gnomad AFR exome

AF:

0.396

Gnomad AMR exome

AF:

0.136

Gnomad ASJ exome

AF:

0.140

Gnomad EAS exome

AF:

0.301

Gnomad SAS exome

AF:

0.166

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.0948

Gnomad OTH exome

AF:

0.137

GnomAD4 exome

AF:

0.117

AC:

170845

AN:

1461402

Hom.:

12981

Cov.:

AF XY:

0.117

AC XY:

85337

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.412

Gnomad4 AMR exome

AF:

0.134

Gnomad4 ASJ exome

AF:

0.146

Gnomad4 EAS exome

AF:

0.321

Gnomad4 SAS exome

AF:

0.164

Gnomad4 FIN exome

AF:

0.115

Gnomad4 NFE exome

AF:

0.0942

Gnomad4 OTH exome

AF:

0.145

GnomAD4 genome

AF:

0.196

AC:

29776

AN:

152064

Hom.:

4245

Cov.:

AF XY:

0.197

AC XY:

14632

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.393

Gnomad4 AMR

AF:

0.140

Gnomad4 ASJ

AF:

0.161

Gnomad4 EAS

AF:

0.301

Gnomad4 SAS

AF:

0.169

Gnomad4 FIN

AF:

0.120

Gnomad4 NFE

AF:

0.0972

Gnomad4 OTH

AF:

0.178

Alfa

AF:

0.0772

Hom.:

141

Bravo

AF:

0.207

EpiCase

AF:

0.0977

EpiControl

AF:

0.0959

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Knobloch syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.012

DANN

Benign

0.39

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