rs695103

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.9379+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,608,182 control chromosomes in the GnomAD database, including 15,074 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 0.11 ( 1115 hom., cov: 33)

Exomes 𝑓: 0.13 ( 13959 hom. )

Consequence

VCAN
NM_004385.5 splice_region, intron

Scores

Splicing: ADA: 0.00001425

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.685

Publications

8 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 5-83545657-T-C is Benign according to our data. Variant chr5-83545657-T-C is described in ClinVar as Benign. ClinVar VariationId is 259377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5 link	c.9379+7T>C		splice_region_variant, intron_variant	Intron 9 of 14	ENST00000265077.8	NP_004376.2	P13611-1A0A024RAQ9Q59FG9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8 link	c.9379+7T>C		splice_region_variant, intron_variant	Intron 9 of 14	1	NM_004385.5	ENSP00000265077.3		P13611-1

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16105

AN:

152120

Hom.:

1113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0529

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0731

Gnomad ASJ

AF:

0.131

Gnomad EAS

AF:

0.226

Gnomad SAS

AF:

0.326

Gnomad FIN

AF:

0.139

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.115

Gnomad OTH

AF:

0.115

GnomAD2 exomes

AF:

0.139

AC:

34968

AN:

251054

AF XY:

0.152

show subpopulations

Gnomad AFR exome

AF:

0.0504

Gnomad AMR exome

AF:

0.0572

Gnomad ASJ exome

AF:

0.140

Gnomad EAS exome

AF:

0.232

Gnomad FIN exome

AF:

0.141

Gnomad NFE exome

AF:

0.114

Gnomad OTH exome

AF:

0.132

GnomAD4 exome

AF:

0.126

AC:

183889

AN:

1455944

Hom.:

13959

Cov.:

AF XY:

0.133

AC XY:

96256

AN XY:

724804

show subpopulations

African (AFR)

AF:

0.0523

AC:

1744

AN:

33316

American (AMR)

AF:

0.0613

AC:

2739

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.136

AC:

3556

AN:

26102

East Asian (EAS)

AF:

0.196

AC:

7753

AN:

39654

South Asian (SAS)

AF:

0.314

AC:

27052

AN:

86158

European-Finnish (FIN)

AF:

0.140

AC:

7476

AN:

53416

Middle Eastern (MID)

AF:

0.186

AC:

1070

AN:

5760

European-Non Finnish (NFE)

AF:

0.112

AC:

124214

AN:

1106608

Other (OTH)

AF:

0.138

AC:

8285

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

8097

16195

24292

32390

40487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4694

9388

14082

18776

23470

<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:

0.106

AC:

16116

AN:

152238

Hom.:

1115

Cov.:

AF XY:

0.113

AC XY:

8426

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0529

AC:

2199

AN:

41560

American (AMR)

AF:

0.0732

AC:

1120

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

454

AN:

3470

East Asian (EAS)

AF:

0.226

AC:

1172

AN:

5176

South Asian (SAS)

AF:

0.327

AC:

1576

AN:

4822

European-Finnish (FIN)

AF:

0.139

AC:

1472

AN:

10590

Middle Eastern (MID)

AF:

0.194

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.115

AC:

7788

AN:

68002

Other (OTH)

AF:

0.114

AC:

242

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

732

1464

2196

2928

3660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

208

416

624

832

1040

<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:

0.112

Hom.:

2069

Bravo

AF:

0.0935

Asia WGS

AF:

0.234

AC:

811

AN:

3476

EpiCase

AF:

0.120

EpiControl

AF:

0.120

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 16, 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

-0.85

CADD

Benign

6.8

(source)

DANN

Benign

0.48

PhyloP100

0.69

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000014

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.11

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