chr5-83512253-C-T

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.899C>T(p.Ser300Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,614,130 control chromosomes in the GnomAD database, including 1,350 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S300S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 141 hom., cov: 32)

Exomes 𝑓: 0.015 ( 1209 hom. )

Consequence

VCAN
NM_004385.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.32

Publications

21 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=0.0040576756).

BP6

Variant 5-83512253-C-T is Benign according to our data. Variant chr5-83512253-C-T is described in CliVar as Benign. Clinvar id is 198170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83512253-C-T is described in CliVar as Benign. Clinvar id is 198170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83512253-C-T is described in CliVar as Benign. Clinvar id is 198170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83512253-C-T is described in CliVar as Benign. Clinvar id is 198170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83512253-C-T is described in CliVar as Benign. Clinvar id is 198170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83512253-C-T is described in CliVar as Benign. Clinvar id is 198170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83512253-C-T is described in CliVar as Benign. Clinvar id is 198170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83512253-C-T is described in CliVar as Benign. Clinvar id is 198170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83512253-C-T is described in CliVar as Benign. Clinvar id is 198170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83512253-C-T is described in CliVar as Benign. Clinvar id is 198170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83512253-C-T is described in CliVar as Benign. Clinvar id is 198170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5 link	c.899C>T	p.Ser300Leu	missense_variant	Exon 6 of 15	ENST00000265077.8	NP_004376.2	P13611-1A0A024RAQ9Q59FG9
VCAN	NM_001164097.2 link	c.899C>T	p.Ser300Leu	missense_variant	Exon 6 of 14		NP_001157569.1	P13611-2A0A024RAL1Q6MZK8
VCAN	NM_001164098.2 link	c.899C>T	p.Ser300Leu	missense_variant	Exon 6 of 14		NP_001157570.1	P13611-3A0A024RAP3
VCAN	NM_001126336.3 link	c.899C>T	p.Ser300Leu	missense_variant	Exon 6 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.899C>T	p.Ser300Leu	missense_variant	Exon 6 of 15	1	NM_004385.5	ENSP00000265077.3		P13611-1

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2275

AN:

152146

Hom.:

143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00454

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00583

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.198

Gnomad SAS

AF:

0.102

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00611

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.0315

AC:

7927

AN:

251294

AF XY:

0.0346

show subpopulations

Gnomad AFR exome

AF:

0.00314

Gnomad AMR exome

AF:

0.00411

Gnomad ASJ exome

AF:

0.00338

Gnomad EAS exome

AF:

0.212

Gnomad FIN exome

AF:

0.000832

Gnomad NFE exome

AF:

0.00622

Gnomad OTH exome

AF:

0.0170

GnomAD4 exome

AF:

0.0151

AC:

22099

AN:

1461866

Hom.:

1209

Cov.:

AF XY:

0.0176

AC XY:

12794

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00460

AC:

154

AN:

33478

American (AMR)

AF:

0.00418

AC:

187

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00367

AC:

AN:

26134

East Asian (EAS)

AF:

0.163

AC:

6453

AN:

39692

South Asian (SAS)

AF:

0.0935

AC:

8062

AN:

86256

European-Finnish (FIN)

AF:

0.00114

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.0257

AC:

148

AN:

5768

European-Non Finnish (NFE)

AF:

0.00498

AC:

5533

AN:

1112002

Other (OTH)

AF:

0.0233

AC:

1405

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1279

2558

3838

5117

6396

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

392

784

1176

1568

1960

<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:

0.0149

AC:

2267

AN:

152264

Hom.:

141

Cov.:

AF XY:

0.0168

AC XY:

1249

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00455

AC:

189

AN:

41558

American (AMR)

AF:

0.00582

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00404

AC:

AN:

3468

East Asian (EAS)

AF:

0.197

AC:

1021

AN:

5170

South Asian (SAS)

AF:

0.102

AC:

491

AN:

4816

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00612

AC:

416

AN:

68026

Other (OTH)

AF:

0.0147

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

197

296

394

493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0108

Hom.:

212

Bravo

AF:

0.0137

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.00605

AC:

ExAC

AF:

0.0323

AC:

3921

Asia WGS

AF:

0.128

AC:

443

AN:

3478

EpiCase

AF:

0.00725

EpiControl

AF:

0.00634

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Wagner syndrome

Benign:2

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

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.067

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.12

T;.;.;T;.;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.83

T;T;T;T;T;T;T

MetaRNN

Benign

0.0041

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;L;L;.;.;.;L

PhyloP100

1.3

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.8

N;D;D;D;D;D;N

REVEL

Benign

0.092

Sift

Benign

0.30

T;T;T;T;T;D;D

Sift4G

Benign

0.18

T;T;T;T;T;T;T

Polyphen

0.010

B;B;B;.;.;B;B

Vest4

0.38

MPC

0.079

ClinPred

0.0031

GERP RS

-3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.043

gMVP

0.86

Mutation Taster

=96/4

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