chr5-83539726-A-G

Position:

• chr5-83539726-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.6723A>G​(p.Arg2241Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 1,613,372 control chromosomes in the GnomAD database, including 190,803 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19064 hom., cov: 32)
  • Exomes 𝑓: 0.48 (171739 hom.)
• Consequence: VCAN NM_004385.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.423

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 5-83539726-A-G is Benign according to our data. Variant chr5-83539726-A-G is described in ClinVar as [Benign]. Clinvar id is 198797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83539726-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.423 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCAN	NM_004385.5	c.6723A>G	p.Arg2241Arg	synonymous_variant	8/15	ENST00000265077.8	NP_004376.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8	c.6723A>G	p.Arg2241Arg	synonymous_variant	8/15	1	NM_004385.5	ENSP00000265077.3

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75894 AN: 151866 Hom.: 19051 Cov.: 32

Gnomad AFR AF: 0.504

Gnomad AMI AF: 0.683

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.493

Gnomad OTH AF: 0.535

GnomAD3 exomes AF: 0.485 AC: 121044 AN: 249592 Hom.: 29626 AF XY: 0.479 AC XY: 64635 AN XY: 134964

Gnomad AFR exome AF: 0.504

Gnomad AMR exome AF: 0.520

Gnomad ASJ exome AF: 0.576

Gnomad EAS exome AF: 0.399

Gnomad SAS exome AF: 0.387

Gnomad FIN exome AF: 0.513

Gnomad NFE exome AF: 0.498

Gnomad OTH exome AF: 0.495

GnomAD4 exome AF: 0.484 AC: 707047 AN: 1461386 Hom.: 171739 Cov.: 72 AF XY: 0.481 AC XY: 349651 AN XY: 726978

Gnomad4 AFR exome AF: 0.499

Gnomad4 AMR exome AF: 0.518

Gnomad4 ASJ exome AF: 0.575

Gnomad4 EAS exome AF: 0.463

Gnomad4 SAS exome AF: 0.389

Gnomad4 FIN exome AF: 0.508

Gnomad4 NFE exome AF: 0.487

Gnomad4 OTH exome AF: 0.480

GnomAD4 genome AF: 0.500 AC: 75941 AN: 151986 Hom.: 19064 Cov.: 32 AF XY: 0.499 AC XY: 37045 AN XY: 74264

Gnomad4 AFR AF: 0.504

Gnomad4 AMR AF: 0.526

Gnomad4 ASJ AF: 0.582

Gnomad4 EAS AF: 0.409

Gnomad4 SAS AF: 0.392

Gnomad4 FIN AF: 0.529

Gnomad4 NFE AF: 0.493

Gnomad4 OTH AF: 0.536

Alfa AF: 0.498 Hom.: 13300

Bravo AF: 0.499

Asia WGS AF: 0.411 AC: 1426 AN: 3478

EpiCase AF: 0.502

EpiControl AF: 0.503

ClinVar

Significance: Benign

Submissions summary: Benign:8

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	Genome-Nilou Lab	Dec 05, 2021	- -
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	Eurofins Ntd Llc (ga)	Jun 12, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 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	-0.86
CADD	Benign	1.1
DANN	Benign	0.62

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: rs160279; hg19: chr5-82835545; COSMIC: COSV54100118; COSMIC: COSV54100118;