NM_004385.5:c.348T>C

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

2

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

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
VCANNM_004385.5 linkc.348T>C p.Thr116Thr synonymous_variant Exon 3 of 15 ENST00000265077.8 NP_004376.2 P13611-1A0A024RAQ9Q59FG9
VCANNM_001164097.2 linkc.348T>C p.Thr116Thr synonymous_variant Exon 3 of 14 NP_001157569.1 P13611-2A0A024RAL1Q6MZK8
VCANNM_001164098.2 linkc.348T>C p.Thr116Thr synonymous_variant Exon 3 of 14 NP_001157570.1 P13611-3A0A024RAP3
VCANNM_001126336.3 linkc.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
VCANENST00000265077.8 linkc.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.:
32
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.:
64
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
0
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
0
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.:
32
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
0
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
0
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
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)

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

Other links and lift over

dbSNP: rs12332199; hg19: chr5-82786194; COSMIC: COSV54097214; API