5-83537550-A-G

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.4547A>G(p.Lys1516Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.486 in 1,613,366 control chromosomes in the GnomAD database, including 191,058 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. K1516E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.50 ( 19170 hom., cov: 31)

Exomes 𝑓: 0.48 ( 171888 hom. )

Consequence

VCAN
NM_004385.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.310

Publications

46 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=4.8598256E-5).

BP6

Variant 5-83537550-A-G is Benign according to our data. Variant chr5-83537550-A-G is described in ClinVar as Benign. ClinVar VariationId is 167820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004385.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VCAN	NM_004385.5	MANE Select	c.4547A>G	p.Lys1516Arg	missense	Exon 8 of 15	NP_004376.2
VCAN	NM_001164097.2		c.1586A>G	p.Lys529Arg	missense	Exon 7 of 14	NP_001157569.1	P13611-2
VCAN	NM_001164098.2		c.4004-7987A>G		intron	N/A	NP_001157570.1	P13611-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VCAN	ENST00000265077.8	TSL:1 MANE Select	c.4547A>G	p.Lys1516Arg	missense	Exon 8 of 15	ENSP00000265077.3	P13611-1
VCAN	ENST00000343200.9	TSL:1	c.1586A>G	p.Lys529Arg	missense	Exon 7 of 14	ENSP00000340062.5	P13611-2
VCAN	ENST00000513960.5	TSL:1	c.1586A>G	p.Lys529Arg	missense	Exon 7 of 7	ENSP00000426251.1	D6RGZ6

Frequencies

GnomAD3 genomes

AF:

0.501

AC:

76040

AN:

151706

Hom.:

19156

Cov.:

show subpopulations

Gnomad AFR

AF:

0.510

Gnomad AMI

AF:

0.681

Gnomad AMR

AF:

0.525

Gnomad ASJ

AF:

0.581

Gnomad EAS

AF:

0.409

Gnomad SAS

AF:

0.394

Gnomad FIN

AF:

0.530

Gnomad MID

AF:

0.503

Gnomad NFE

AF:

0.493

Gnomad OTH

AF:

0.536

GnomAD2 exomes

AF:

0.485

AC:

121133

AN:

249592

AF XY:

0.479

show subpopulations

Gnomad AFR exome

AF:

0.509

Gnomad AMR exome

AF:

0.520

Gnomad ASJ exome

AF:

0.575

Gnomad EAS exome

AF:

0.399

Gnomad FIN exome

AF:

0.513

Gnomad NFE exome

AF:

0.499

Gnomad OTH exome

AF:

0.496

GnomAD4 exome

AF:

0.484

AC:

707325

AN:

1461542

Hom.:

171888

Cov.:

AF XY:

0.481

AC XY:

349777

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.504

AC:

16858

AN:

33468

American (AMR)

AF:

0.518

AC:

23135

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.575

AC:

15016

AN:

26128

East Asian (EAS)

AF:

0.463

AC:

18377

AN:

39676

South Asian (SAS)

AF:

0.389

AC:

33586

AN:

86256

European-Finnish (FIN)

AF:

0.508

AC:

27111

AN:

53376

Middle Eastern (MID)

AF:

0.503

AC:

2900

AN:

5768

European-Non Finnish (NFE)

AF:

0.487

AC:

541333

AN:

1111848

Other (OTH)

AF:

0.480

AC:

29009

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

24441

48882

73324

97765

122206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15874

31748

47622

63496

79370

<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:

0.501

AC:

76093

AN:

151824

Hom.:

19170

Cov.:

AF XY:

0.500

AC XY:

37108

AN XY:

74172

show subpopulations

African (AFR)

AF:

0.510

AC:

21122

AN:

41408

American (AMR)

AF:

0.525

AC:

7992

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.581

AC:

2015

AN:

3466

East Asian (EAS)

AF:

0.409

AC:

2108

AN:

5150

South Asian (SAS)

AF:

0.392

AC:

1881

AN:

4800

European-Finnish (FIN)

AF:

0.530

AC:

5579

AN:

10526

Middle Eastern (MID)

AF:

0.500

AC:

146

AN:

292

European-Non Finnish (NFE)

AF:

0.493

AC:

33497

AN:

67926

Other (OTH)

AF:

0.537

AC:

1132

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1965

3929

5894

7858

9823

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

672

1344

2016

2688

3360

<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:

0.497

Hom.:

58063

Bravo

AF:

0.500

TwinsUK

AF:

0.489

AC:

1815

ALSPAC

AF:

0.485

AC:

1868

ESP6500AA

AF:

0.505

AC:

2227

ESP6500EA

AF:

0.495

AC:

4258

ExAC

AF:

0.483

AC:

58635

Asia WGS

AF:

0.412

AC:

1432

AN:

3478

EpiCase

AF:

0.502

EpiControl

AF:

0.503

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Wagner disease (3)

not provided (2)

not specified (2)

Vitreoretinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

1.7

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.10

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.27

MetaRNN

Benign

0.000049

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

PhyloP100

0.31

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.37

REVEL

Benign

0.085

Sift

Benign

0.11

Sift4G

Benign

0.48

Polyphen

0.011

Vest4

0.024

MPC

0.065

ClinPred

0.0080

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.040

gMVP

0.056

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over