rs35648048

chr5-83538190-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004385.5(VCAN):c.5187G>A(p.Glu1729=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00424 in 1,613,868 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (26 hom.)
• Consequence: VCAN NM_004385.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.776

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)

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-83538190-G-A is Benign according to our data. Variant chr5-83538190-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 167822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83538190-G-A is described in Lovd as [Benign]. Variant chr5-83538190-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.776 with no splicing effect.
• BS2: High AC in GnomAd at 446 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCAN	NM_004385.5	c.5187G>A	p.Glu1729=	synonymous_variant	8/15	ENST00000265077.8
VCAN-AS1	NR_136215.1	n.285-4017C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCAN	ENST00000265077.8	c.5187G>A	p.Glu1729=	synonymous_variant	8/15	1	NM_004385.5

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 446 AN: 152164 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00448

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00211 AC: 527 AN: 249722 Hom.: 0 AF XY: 0.00193 AC XY: 261 AN XY: 135246

Gnomad AFR exome AF: 0.00127

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00369

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00438 AC: 6401 AN: 1461586 Hom.: 26 Cov.: 77 AF XY: 0.00422 AC XY: 3070 AN XY: 727086

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000207

Gnomad4 NFE exome AF: 0.00542

Gnomad4 OTH exome AF: 0.00369

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152282 Hom.: 2 Cov.: 32 AF XY: 0.00275 AC XY: 205 AN XY: 74458

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00448

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00338 Hom.: 1

Bravo AF: 0.00305

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00433

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 06, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Wagner syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Nov 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	VCAN: BP4, BP7, BS1, BS2 -

Vitreoretinopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.81
Cadd	Benign	5.3
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs35648048; hg19: chr5-82834009;