NM_004385.5:c.5477G>A

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.5477G>A(p.Arg1826His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,613,642 control chromosomes in the GnomAD database, including 117,577 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1826P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.38 ( 11307 hom., cov: 32)

Exomes 𝑓: 0.38 ( 106270 hom. )

Consequence

VCAN
NM_004385.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.74

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 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 (MetaRNN=2.5302172E-4).

BP6

Variant 5-83538480-G-A is Benign according to our data. Variant chr5-83538480-G-A is described in CliVar as Benign. Clinvar id is 167823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83538480-G-A is described in CliVar as Benign. Clinvar id is 167823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83538480-G-A is described in CliVar as Benign. Clinvar id is 167823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83538480-G-A is described in CliVar as Benign. Clinvar id is 167823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83538480-G-A is described in CliVar as Benign. Clinvar id is 167823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83538480-G-A is described in CliVar as Benign. Clinvar id is 167823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83538480-G-A is described in CliVar as Benign. Clinvar id is 167823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83538480-G-A is described in CliVar as Benign. Clinvar id is 167823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83538480-G-A is described in CliVar as Benign. Clinvar id is 167823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83538480-G-A is described in CliVar as Benign. Clinvar id is 167823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5 link	c.5477G>A	p.Arg1826His	missense_variant	Exon 8 of 15	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.5477G>A	p.Arg1826His	missense_variant	Exon 8 of 15	1	NM_004385.5	ENSP00000265077.3		P13611-1

Frequencies

GnomAD3 genomes

AF:

0.382

AC:

58020

AN:

151798

Hom.:

11303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.352

Gnomad AMI

AF:

0.502

Gnomad AMR

AF:

0.437

Gnomad ASJ

AF:

0.481

Gnomad EAS

AF:

0.352

Gnomad SAS

AF:

0.271

Gnomad FIN

AF:

0.402

Gnomad MID

AF:

0.411

Gnomad NFE

AF:

0.387

Gnomad OTH

AF:

0.417

GnomAD2 exomes

AF:

0.384

AC:

96019

AN:

250096

AF XY:

0.378

show subpopulations

Gnomad AFR exome

AF:

0.349

Gnomad AMR exome

AF:

0.457

Gnomad ASJ exome

AF:

0.482

Gnomad EAS exome

AF:

0.344

Gnomad FIN exome

AF:

0.390

Gnomad NFE exome

AF:

0.392

Gnomad OTH exome

AF:

0.396

GnomAD4 exome

AF:

0.379

AC:

554355

AN:

1461726

Hom.:

106270

Cov.:

AF XY:

0.376

AC XY:

273669

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.344

AC:

11501

AN:

33474

American (AMR)

AF:

0.454

AC:

20271

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.480

AC:

12549

AN:

26130

East Asian (EAS)

AF:

0.410

AC:

16286

AN:

39692

South Asian (SAS)

AF:

0.275

AC:

23717

AN:

86256

European-Finnish (FIN)

AF:

0.388

AC:

20704

AN:

53398

Middle Eastern (MID)

AF:

0.419

AC:

2418

AN:

5766

European-Non Finnish (NFE)

AF:

0.382

AC:

424407

AN:

1111932

Other (OTH)

AF:

0.373

AC:

22502

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

23057

46114

69171

92228

115285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13286

26572

39858

53144

66430

<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:

0.382

AC:

58041

AN:

151916

Hom.:

11307

Cov.:

AF XY:

0.380

AC XY:

28220

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.352

AC:

14560

AN:

41414

American (AMR)

AF:

0.437

AC:

6671

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.481

AC:

1671

AN:

3472

East Asian (EAS)

AF:

0.352

AC:

1812

AN:

5146

South Asian (SAS)

AF:

0.271

AC:

1304

AN:

4818

European-Finnish (FIN)

AF:

0.402

AC:

4250

AN:

10568

Middle Eastern (MID)

AF:

0.408

AC:

120

AN:

294

European-Non Finnish (NFE)

AF:

0.387

AC:

26322

AN:

67938

Other (OTH)

AF:

0.416

AC:

875

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1832

3664

5495

7327

9159

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:

0.383

Hom.:

34441

Bravo

AF:

0.385

TwinsUK

AF:

0.389

AC:

1441

ALSPAC

AF:

0.378

AC:

1457

ESP6500AA

AF:

0.352

AC:

1549

ESP6500EA

AF:

0.400

AC:

3441

ExAC

AF:

0.380

AC:

46087

Asia WGS

AF:

0.284

AC:

986

AN:

3476

EpiCase

AF:

0.400

EpiControl

AF:

0.399

ClinVar

Significance: Benign

Submissions summary: Benign:8

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 specified

Benign:2

Jan 20, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 14, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19655167) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Vitreoretinopathy

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.089

T;.;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.37

T;T;T

MetaRNN

Benign

0.00025

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.

PhyloP100

1.7

PrimateAI

Benign

0.23

PROVEAN

Benign

0.18

N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.0020

D;D;D

Sift4G

Benign

0.55

T;T;T

Polyphen

0.23

B;B;.

Vest4

0.034

MPC

0.098

ClinPred

0.020

GERP RS

0.25

Varity_R

0.059

gMVP

0.19

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