rs3096171

Positions:

chr5-83541625-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004385.5(VCAN):c.8622G>A(p.Ala2874=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,613,724 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 47 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 18 hom. )

Consequence

VCAN
NM_004385.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.936

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 made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 5-83541625-G-A is Benign according to our data. Variant chr5-83541625-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 198799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.936 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0114 (1738/152182) while in subpopulation AFR AF= 0.0396 (1642/41512). AF 95% confidence interval is 0.038. There are 47 homozygotes in gnomad4. There are 855 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1738 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCAN	NM_004385.5 linkuse as main transcript	c.8622G>A	p.Ala2874=	synonymous_variant	8/15	ENST00000265077.8
VCAN-AS1	NR_136215.1 linkuse as main transcript	n.285-7452C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCAN	ENST00000265077.8 linkuse as main transcript	c.8622G>A	p.Ala2874=	synonymous_variant	8/15	1	NM_004385.5		P13611-1
VCAN-AS1	ENST00000513899.1 linkuse as main transcript	n.305C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1730

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0395

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00479

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00719

GnomAD3 exomes

AF:

0.00306

AC:

766

AN:

249928

Hom.:

AF XY:

0.00232

AC XY:

313

AN XY:

135138

show subpopulations

Gnomad AFR exome

AF:

0.0389

Gnomad AMR exome

AF:

0.00289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000222

Gnomad OTH exome

AF:

0.000983

GnomAD4 exome

AF:

0.00124

AC:

1812

AN:

1461542

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

798

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.0388

Gnomad4 AMR exome

AF:

0.00364

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000153

Gnomad4 OTH exome

AF:

0.00258

GnomAD4 genome

AF:

0.0114

AC:

1738

AN:

152182

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

855

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0396

Gnomad4 AMR

AF:

0.00478

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00712

Alfa

AF:

0.00453

Hom.:

Bravo

AF:

0.0131

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wagner syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 20, 2014	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Vitreoretinopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

-0.79

CADD

Benign

0.32

DANN

Benign

0.76

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over