rs2287926

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004385.5(VCAN):c.1283G>A(p.Gly428Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,613,872 control chromosomes in the GnomAD database, including 16,434 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2613 hom., cov: 33)

Exomes 𝑓: 0.13 ( 13821 hom. )

Consequence

VCAN
NM_004385.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.550

Publications

41 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0054662824).

BP6

Variant 5-83519589-G-A is Benign according to our data. Variant chr5-83519589-G-A is described in ClinVar as Benign. ClinVar VariationId is 259361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5 link	c.1283G>A	p.Gly428Asp	missense_variant	Exon 7 of 15	ENST00000265077.8	NP_004376.2	P13611-1A0A024RAQ9Q59FG9
VCAN	NM_001164098.2 link	c.1283G>A	p.Gly428Asp	missense_variant	Exon 7 of 14		NP_001157570.1	P13611-3A0A024RAP3
VCAN	NM_001164097.2 link	c.1042+7193G>A		intron_variant	Intron 6 of 13		NP_001157569.1	P13611-2A0A024RAL1Q6MZK8
VCAN	NM_001126336.3 link	c.1042+7193G>A		intron_variant	Intron 6 of 12		NP_001119808.1	P13611-4Q86W61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8 link	c.1283G>A	p.Gly428Asp	missense_variant	Exon 7 of 15	1	NM_004385.5	ENSP00000265077.3		P13611-1

Frequencies

GnomAD3 genomes

AF:

0.169

AC:

25704

AN:

151944

Hom.:

2613

Cov.:

show subpopulations

Gnomad AFR

AF:

0.277

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.142

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.177

Gnomad SAS

AF:

0.226

Gnomad FIN

AF:

0.112

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.117

Gnomad OTH

AF:

0.157

GnomAD2 exomes

AF:

0.149

AC:

37335

AN:

251100

AF XY:

0.150

show subpopulations

Gnomad AFR exome

AF:

0.282

Gnomad AMR exome

AF:

0.134

Gnomad ASJ exome

AF:

0.135

Gnomad EAS exome

AF:

0.173

Gnomad FIN exome

AF:

0.104

Gnomad NFE exome

AF:

0.118

Gnomad OTH exome

AF:

0.133

GnomAD4 exome

AF:

0.130

AC:

190217

AN:

1461810

Hom.:

13821

Cov.:

AF XY:

0.132

AC XY:

96226

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.288

AC:

9639

AN:

33480

American (AMR)

AF:

0.135

AC:

6024

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.136

AC:

3566

AN:

26134

East Asian (EAS)

AF:

0.176

AC:

6977

AN:

39698

South Asian (SAS)

AF:

0.231

AC:

19962

AN:

86256

European-Finnish (FIN)

AF:

0.100

AC:

5361

AN:

53418

Middle Eastern (MID)

AF:

0.181

AC:

1042

AN:

5768

European-Non Finnish (NFE)

AF:

0.116

AC:

129039

AN:

1111942

Other (OTH)

AF:

0.143

AC:

8607

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

11351

22702

34052

45403

56754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4884

9768

14652

19536

24420

<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:

0.169

AC:

25717

AN:

152062

Hom.:

2613

Cov.:

AF XY:

0.170

AC XY:

12612

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.276

AC:

11447

AN:

41452

American (AMR)

AF:

0.142

AC:

2170

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

469

AN:

3468

East Asian (EAS)

AF:

0.177

AC:

917

AN:

5172

South Asian (SAS)

AF:

0.226

AC:

1087

AN:

4816

European-Finnish (FIN)

AF:

0.112

AC:

1180

AN:

10582

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.117

AC:

7967

AN:

67986

Other (OTH)

AF:

0.159

AC:

335

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1060

2121

3181

4242

5302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

280

560

840

1120

1400

<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:

0.138

Hom.:

8252

Bravo

AF:

0.177

TwinsUK

AF:

0.110

AC:

409

ALSPAC

AF:

0.121

AC:

465

ESP6500AA

AF:

0.279

AC:

1229

ESP6500EA

AF:

0.114

AC:

984

ExAC

AF:

0.153

AC:

18530

Asia WGS

AF:

0.223

AC:

781

AN:

3478

EpiCase

AF:

0.128

EpiControl

AF:

0.126

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wagner syndrome

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 02, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25606449) -

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

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.22

T;.;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.71

T;T;T

MetaRNN

Benign

0.0055

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;M;.

PhyloP100

0.55

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.93

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.046

D;D;D

Sift4G

Benign

0.39

T;T;T

Polyphen

0.99

D;P;.

Vest4

0.17

MPC

0.37

ClinPred

0.012

GERP RS

0.92

Varity_R

0.054

gMVP

0.13

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