NM_004385.5:c.5477G>A

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

1
17

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-AS1 (HGNC:40163): (VCAN antisense RNA 1)

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
VCANNM_004385.5 linkc.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
VCANENST00000265077.8 linkc.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.:
32
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.:
74
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
0
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
0
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.:
32
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
0
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
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:
0.383
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
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
12
DANN
Benign
0.82
DEOGEN2
Benign
0.089
T;.;.
Eigen
Benign
-0.86
Eigen_PC
Benign
-0.88
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.37
T;T;T
MetaRNN
Benign
0.00025
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;.;.
PhyloP100
1.7
PrimateAI
Benign
0.23
T
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
T
GERP RS
0.25
Varity_R
0.059
gMVP
0.19
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: rs188703; hg19: chr5-82834299; COSMIC: COSV54100100; COSMIC: COSV54100100; API