rs308365

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.9882C>T(p.Val3294Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.967 in 1,614,062 control chromosomes in the GnomAD database, including 755,470 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.97 ( 72263 hom., cov: 33)

Exomes 𝑓: 0.97 ( 683207 hom. )

Consequence

VCAN
NM_004385.5 splice_region, synonymous

Scores

Splicing: ADA: 0.00006417

Clinical Significance

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

Conservation

PhyloP100: 0.797

Publications

23 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 links:

VCAN-AS1 (HGNC:40163): (VCAN antisense RNA 1)

VCAN-AS1 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=-0.49).

BP6

Variant 5-83579981-C-T is Benign according to our data. Variant chr5-83579981-C-T is described in ClinVar as [Benign]. Clinvar id is 259379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.797 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5 link	c.9882C>T	p.Val3294Val	splice_region_variant, synonymous_variant	Exon 14 of 15	ENST00000265077.8	NP_004376.2	P13611-1A0A024RAQ9Q59FG9
VCAN	NM_001164097.2 link	c.6921C>T	p.Val2307Val	splice_region_variant, synonymous_variant	Exon 13 of 14		NP_001157569.1	P13611-2A0A024RAL1Q6MZK8
VCAN	NM_001164098.2 link	c.4620C>T	p.Val1540Val	splice_region_variant, synonymous_variant	Exon 13 of 14		NP_001157570.1	P13611-3A0A024RAP3
VCAN	NM_001126336.3 link	c.1659C>T	p.Val553Val	splice_region_variant, synonymous_variant	Exon 12 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.9882C>T	p.Val3294Val	splice_region_variant, synonymous_variant	Exon 14 of 15	1	NM_004385.5	ENSP00000265077.3		P13611-1

Frequencies

GnomAD3 genomes

AF:

0.974

AC:

148231

AN:

152204

Hom.:

72201

Cov.:

show subpopulations

Gnomad AFR

AF:

0.993

Gnomad AMI

AF:

0.946

Gnomad AMR

AF:

0.975

Gnomad ASJ

AF:

0.978

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.993

Gnomad FIN

AF:

0.963

Gnomad MID

AF:

0.972

Gnomad NFE

AF:

0.960

Gnomad OTH

AF:

0.978

GnomAD2 exomes

AF:

0.975

AC:

244924

AN:

251108

AF XY:

0.975

show subpopulations

Gnomad AFR exome

AF:

0.993

Gnomad AMR exome

AF:

0.989

Gnomad ASJ exome

AF:

0.983

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.958

Gnomad NFE exome

AF:

0.964

Gnomad OTH exome

AF:

0.972

GnomAD4 exome

AF:

0.967

AC:

1413159

AN:

1461740

Hom.:

683207

Cov.:

AF XY:

0.967

AC XY:

703263

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.994

AC:

33275

AN:

33470

American (AMR)

AF:

0.988

AC:

44159

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.983

AC:

25686

AN:

26130

East Asian (EAS)

AF:

1.00

AC:

39684

AN:

39686

South Asian (SAS)

AF:

0.991

AC:

85471

AN:

86258

European-Finnish (FIN)

AF:

0.957

AC:

51146

AN:

53420

Middle Eastern (MID)

AF:

0.973

AC:

5611

AN:

5764

European-Non Finnish (NFE)

AF:

0.962

AC:

1069502

AN:

1111910

Other (OTH)

AF:

0.971

AC:

58625

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

2538

5076

7614

10152

12690

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.974

AC:

148352

AN:

152322

Hom.:

72263

Cov.:

AF XY:

0.975

AC XY:

72573

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.993

AC:

41272

AN:

41574

American (AMR)

AF:

0.975

AC:

14924

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.978

AC:

3396

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5181

AN:

5182

South Asian (SAS)

AF:

0.993

AC:

4793

AN:

4828

European-Finnish (FIN)

AF:

0.963

AC:

10224

AN:

10612

Middle Eastern (MID)

AF:

0.976

AC:

287

AN:

294

European-Non Finnish (NFE)

AF:

0.960

AC:

65342

AN:

68032

Other (OTH)

AF:

0.978

AC:

2070

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

205

410

616

821

1026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.968

Hom.:

192868

Bravo

AF:

0.976

Asia WGS

AF:

0.997

AC:

3466

AN:

3478

EpiCase

AF:

0.964

EpiControl

AF:

0.966

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

- -

Nov 19, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

May 05, 2021

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

-0.49

CADD

Benign

9.6

(source)

DANN

Benign

0.86

PhyloP100

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=53/47

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000064

dbscSNV1_RF

Benign

0.014

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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rs308365

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