NM_004385.5:c.348T>C

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.348T>C(p.Thr116Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,613,948 control chromosomes in the GnomAD database, including 113,270 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12083 hom., cov: 32)

Exomes 𝑓: 0.37 ( 101187 hom. )

Consequence

VCAN
NM_004385.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.10

Publications

17 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 (BayesDel_noAF=-0.85).

BP6

Variant 5-83490375-T-C is Benign according to our data. Variant chr5-83490375-T-C is described in ClinVar as [Benign]. Clinvar id is 259363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5 link	c.348T>C	p.Thr116Thr	synonymous_variant	Exon 3 of 15	ENST00000265077.8	NP_004376.2	P13611-1A0A024RAQ9Q59FG9
VCAN	NM_001164097.2 link	c.348T>C	p.Thr116Thr	synonymous_variant	Exon 3 of 14		NP_001157569.1	P13611-2A0A024RAL1Q6MZK8
VCAN	NM_001164098.2 link	c.348T>C	p.Thr116Thr	synonymous_variant	Exon 3 of 14		NP_001157570.1	P13611-3A0A024RAP3
VCAN	NM_001126336.3 link	c.348T>C	p.Thr116Thr	synonymous_variant	Exon 3 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.348T>C	p.Thr116Thr	synonymous_variant	Exon 3 of 15	1	NM_004385.5	ENSP00000265077.3		P13611-1

Frequencies

GnomAD3 genomes

AF:

0.393

AC:

59756

AN:

151976

Hom.:

12080

Cov.:

show subpopulations

Gnomad AFR

AF:

0.479

Gnomad AMI

AF:

0.405

Gnomad AMR

AF:

0.388

Gnomad ASJ

AF:

0.321

Gnomad EAS

AF:

0.179

Gnomad SAS

AF:

0.237

Gnomad FIN

AF:

0.374

Gnomad MID

AF:

0.359

Gnomad NFE

AF:

0.377

Gnomad OTH

AF:

0.380

GnomAD2 exomes

AF:

0.351

AC:

88073

AN:

251014

AF XY:

0.343

show subpopulations

Gnomad AFR exome

AF:

0.476

Gnomad AMR exome

AF:

0.404

Gnomad ASJ exome

AF:

0.324

Gnomad EAS exome

AF:

0.179

Gnomad FIN exome

AF:

0.383

Gnomad NFE exome

AF:

0.371

Gnomad OTH exome

AF:

0.362

GnomAD4 exome

AF:

0.368

AC:

537828

AN:

1461854

Hom.:

101187

Cov.:

AF XY:

0.363

AC XY:

264255

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.486

AC:

16272

AN:

33480

American (AMR)

AF:

0.404

AC:

18087

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.326

AC:

8528

AN:

26134

East Asian (EAS)

AF:

0.153

AC:

6093

AN:

39698

South Asian (SAS)

AF:

0.242

AC:

20860

AN:

86258

European-Finnish (FIN)

AF:

0.378

AC:

20163

AN:

53402

Middle Eastern (MID)

AF:

0.356

AC:

2051

AN:

5768

European-Non Finnish (NFE)

AF:

0.381

AC:

424124

AN:

1111996

Other (OTH)

AF:

0.358

AC:

21650

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

21752

43504

65257

87009

108761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13388

26776

40164

53552

66940

<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:

0.393

AC:

59790

AN:

152094

Hom.:

12083

Cov.:

AF XY:

0.390

AC XY:

29012

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.478

AC:

19836

AN:

41464

American (AMR)

AF:

0.388

AC:

5930

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

1112

AN:

3468

East Asian (EAS)

AF:

0.179

AC:

927

AN:

5176

South Asian (SAS)

AF:

0.236

AC:

1139

AN:

4826

European-Finnish (FIN)

AF:

0.374

AC:

3960

AN:

10576

Middle Eastern (MID)

AF:

0.359

AC:

104

AN:

290

European-Non Finnish (NFE)

AF:

0.377

AC:

25616

AN:

67982

Other (OTH)

AF:

0.378

AC:

797

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1855

3709

5564

7418

9273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

560

1120

1680

2240

2800

<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:

0.369

Hom.:

8536

Bravo

AF:

0.401

Asia WGS

AF:

0.242

AC:

845

AN:

3478

EpiCase

AF:

0.369

EpiControl

AF:

0.372

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wagner syndrome

Benign:3

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 02, 2018

GeneDx

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

2.8

(source)

DANN

Benign

0.23

PhyloP100

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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