rs4470745

Positions:

• chr5-83493828-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004385.5(VCAN):​c.645A>G​(p.Val215=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,613,894 control chromosomes in the GnomAD database, including 118,135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8925 hom., cov: 32)
  • Exomes 𝑓: 0.38 (109210 hom.)
• Consequence: VCAN NM_004385.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.282

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 5-83493828-A-G is Benign according to our data. Variant chr5-83493828-A-G is described in ClinVar as [Benign]. Clinvar id is 259373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83493828-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.282 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCAN	NM_004385.5	c.645A>G	p.Val215=	synonymous_variant	5/15	ENST00000265077.8	NP_004376.2
VCAN	NM_001164097.2	c.645A>G	p.Val215=	synonymous_variant	5/14		NP_001157569.1
VCAN	NM_001164098.2	c.645A>G	p.Val215=	synonymous_variant	5/14		NP_001157570.1
VCAN	NM_001126336.3	c.645A>G	p.Val215=	synonymous_variant	5/13		NP_001119808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8	c.645A>G	p.Val215=	synonymous_variant	5/15	1	NM_004385.5	ENSP00000265077

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50285 AN: 151934 Hom.: 8930 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.0792

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.320

GnomAD3 exomes AF: 0.322 AC: 80932 AN: 251278 Hom.: 14347 AF XY: 0.325 AC XY: 44077 AN XY: 135790

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.270

Gnomad ASJ exome AF: 0.364

Gnomad EAS exome AF: 0.0686

Gnomad SAS exome AF: 0.238

Gnomad FIN exome AF: 0.376

Gnomad NFE exome AF: 0.398

Gnomad OTH exome AF: 0.356

GnomAD4 exome AF: 0.379 AC: 554125 AN: 1461842 Hom.: 109210 Cov.: 63 AF XY: 0.376 AC XY: 273369 AN XY: 727224

Gnomad4 AFR exome AF: 0.240

Gnomad4 AMR exome AF: 0.279

Gnomad4 ASJ exome AF: 0.361

Gnomad4 EAS exome AF: 0.0545

Gnomad4 SAS exome AF: 0.244

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.411

Gnomad4 OTH exome AF: 0.355

GnomAD4 genome AF: 0.331 AC: 50274 AN: 152052 Hom.: 8925 Cov.: 32 AF XY: 0.326 AC XY: 24212 AN XY: 74310

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.306

Gnomad4 ASJ AF: 0.353

Gnomad4 EAS AF: 0.0794

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.373

Gnomad4 NFE AF: 0.407

Gnomad4 OTH AF: 0.318

Alfa AF: 0.383 Hom.: 18666

Bravo AF: 0.322

Asia WGS AF: 0.181 AC: 631 AN: 3478

EpiCase AF: 0.403

EpiControl AF: 0.400

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

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	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	-0.59
CADD	Benign	9.8
DANN	Benign	0.75

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

Other links and lift over

dbSNP: rs4470745; hg19: chr5-82789647; COSMIC: COSV54104482;