Genetic Variant VCAN:p.Thr1719Ser (chr5-83538158-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004385.5(VCAN):c.5155A>T(p.Thr1719Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,613,918 control chromosomes in the GnomAD database, including 88 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 (★★).

Frequency

Genomes: 𝑓 0.012 ( 39 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 49 hom. )

Consequence

VCAN
NM_004385.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.20

Publications

3 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=0.00195539).

BP6

Variant 5-83538158-A-T is Benign according to our data. Variant chr5-83538158-A-T is described in ClinVar as Benign. ClinVar VariationId is 259367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0122 (1865/152254) while in subpopulation AFR AF = 0.0426 (1770/41558). AF 95% confidence interval is 0.0409. There are 39 homozygotes in GnomAd4. There are 885 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1865 AD gene.

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
VCAN	NM_004385.5	MANE Select	c.5155A>T	p.Thr1719Ser	missense	Exon 8 of 15	NP_004376.2
VCAN	NM_001164097.2		c.2194A>T	p.Thr732Ser	missense	Exon 7 of 14	NP_001157569.1
VCAN	NM_001164098.2		c.4004-7379A>T		intron	N/A	NP_001157570.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VCAN	ENST00000265077.8	TSL:1 MANE Select	c.5155A>T	p.Thr1719Ser	missense	Exon 8 of 15	ENSP00000265077.3
VCAN	ENST00000343200.9	TSL:1	c.2194A>T	p.Thr732Ser	missense	Exon 7 of 14	ENSP00000340062.5
VCAN	ENST00000513960.5	TSL:1	c.2194A>T	p.Thr732Ser	missense	Exon 7 of 7	ENSP00000426251.1

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1849

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0423

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00511

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00292

AC:

729

AN:

249644

AF XY:

0.00225

show subpopulations

Gnomad AFR exome

AF:

0.0428

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.00129

AC:

1891

AN:

1461664

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

840

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.0460

AC:

1540

AN:

33470

American (AMR)

AF:

0.00197

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.000128

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000504

AC:

AN:

1111946

Other (OTH)

AF:

0.00308

AC:

186

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

132

264

395

527

659

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.0122

AC:

1865

AN:

152254

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

885

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0426

AC:

1770

AN:

41558

American (AMR)

AF:

0.00510

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68002

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

179

269

358

448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00200

Hom.:

Bravo

AF:

0.0148

ESP6500AA

AF:

0.0377

AC:

166

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00348

AC:

422

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Wagner disease (2)

not provided (1)

not specified (1)

Vitreoretinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.011

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.076

Eigen

Benign

-2.0

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0054

LIST_S2

Benign

0.16

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.85

PhyloP100

-1.2

PrimateAI

Benign

0.23

PROVEAN

Benign

0.58

REVEL

Benign

0.097

Sift

Benign

1.0

Sift4G

Benign

0.93

Polyphen

0.0

Vest4

0.064

MutPred

0.060

Loss of glycosylation at T1719 (P = 0.0506)

MVP

0.27

MPC

0.071

ClinPred

0.0024

GERP RS

-2.6

Varity_R

0.017

gMVP

0.046

Mutation Taster

=99/1

polymorphism

(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