rs4470745

Variant names:

Variant summary

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

The NM_004385.5(VCAN):c.645A>G(p.Val215Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,613,894 control chromosomes in the GnomAD database, including 118,135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8925 hom., cov: 32)

Exomes 𝑓: 0.38 ( 109210 hom. )

Consequence

VCAN
NM_004385.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.282

Publications

19 publications found

Variant links:

Genes affected

VCAN (HGNC:2464): (versican) This gene is a member of the aggrecan/versican proteoglycan family. The protein encoded is a large chondroitin sulfate proteoglycan and is a major component of the extracellular matrix. This protein is involved in cell adhesion, proliferation, proliferation, migration and angiogenesis and plays a central role in tissue morphogenesis and maintenance. Mutations in this gene are the cause of Wagner syndrome type 1. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2009]

VCAN Gene-Disease associations (from GenCC):

Wagner disease
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

VCAN 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=-0.59).

BP6

Variant 5-83493828-A-G is Benign according to our data. Variant chr5-83493828-A-G is described in ClinVar as Benign. ClinVar VariationId is 259373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.282 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5 link	c.645A>G	p.Val215Val	synonymous_variant	Exon 5 of 15	ENST00000265077.8	NP_004376.2	P13611-1A0A024RAQ9Q59FG9
VCAN	NM_001164097.2 link	c.645A>G	p.Val215Val	synonymous_variant	Exon 5 of 14		NP_001157569.1	P13611-2A0A024RAL1Q6MZK8
VCAN	NM_001164098.2 link	c.645A>G	p.Val215Val	synonymous_variant	Exon 5 of 14		NP_001157570.1	P13611-3A0A024RAP3
VCAN	NM_001126336.3 link	c.645A>G	p.Val215Val	synonymous_variant	Exon 5 of 13		NP_001119808.1	P13611-4Q86W61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8 link	c.645A>G	p.Val215Val	synonymous_variant	Exon 5 of 15	1	NM_004385.5	ENSP00000265077.3		P13611-1

Frequencies

GnomAD3 genomes

AF:

0.331

AC:

50285

AN:

151934

Hom.:

8930

Cov.:

show subpopulations

Gnomad AFR

AF:

0.243

Gnomad AMI

AF:

0.441

Gnomad AMR

AF:

0.306

Gnomad ASJ

AF:

0.353

Gnomad EAS

AF:

0.0792

Gnomad SAS

AF:

0.234

Gnomad FIN

AF:

0.373

Gnomad MID

AF:

0.328

Gnomad NFE

AF:

0.407

Gnomad OTH

AF:

0.320

GnomAD2 exomes

AF:

0.322

AC:

80932

AN:

251278

AF XY:

0.325

show subpopulations

Gnomad AFR exome

AF:

0.240

Gnomad AMR exome

AF:

0.270

Gnomad ASJ exome

AF:

0.364

Gnomad EAS exome

AF:

0.0686

Gnomad FIN exome

AF:

0.376

Gnomad NFE exome

AF:

0.398

Gnomad OTH exome

AF:

0.356

GnomAD4 exome

AF:

0.379

AC:

554125

AN:

1461842

Hom.:

109210

Cov.:

AF XY:

0.376

AC XY:

273369

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.240

AC:

8036

AN:

33480

American (AMR)

AF:

0.279

AC:

12481

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.361

AC:

9446

AN:

26134

East Asian (EAS)

AF:

0.0545

AC:

2165

AN:

39698

South Asian (SAS)

AF:

0.244

AC:

21072

AN:

86256

European-Finnish (FIN)

AF:

0.375

AC:

20012

AN:

53416

Middle Eastern (MID)

AF:

0.331

AC:

1907

AN:

5768

European-Non Finnish (NFE)

AF:

0.411

AC:

457570

AN:

1111978

Other (OTH)

AF:

0.355

AC:

21436

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

23805

47610

71416

95221

119026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13934

27868

41802

55736

69670

<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:

0.331

AC:

50274

AN:

152052

Hom.:

8925

Cov.:

AF XY:

0.326

AC XY:

24212

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.243

AC:

10062

AN:

41468

American (AMR)

AF:

0.306

AC:

4676

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.353

AC:

1227

AN:

3472

East Asian (EAS)

AF:

0.0794

AC:

411

AN:

5178

South Asian (SAS)

AF:

0.234

AC:

1127

AN:

4822

European-Finnish (FIN)

AF:

0.373

AC:

3934

AN:

10552

Middle Eastern (MID)

AF:

0.322

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.407

AC:

27669

AN:

67966

Other (OTH)

AF:

0.318

AC:

673

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1695

3390

5086

6781

8476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

496

992

1488

1984

2480

<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:

0.382

Hom.:

21378

Bravo

AF:

0.322

Asia WGS

AF:

0.181

AC:

631

AN:

3478

EpiCase

AF:

0.403

EpiControl

AF:

0.400

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wagner syndrome

Benign:3

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Sep 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Vitreoretinopathy

Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

9.8

(source)

DANN

Benign

0.75

PhyloP100

0.28

Mutation Taster

=99/1

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