rs139453864

chr5-83542237-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_004385.5(VCAN):c.9234G>A(p.Glu3078=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,613,758 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (12 hom.)
• Consequence: VCAN NM_004385.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.215

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 5-83542237-G-A is Benign according to our data. Variant chr5-83542237-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83542237-G-A is described in Lovd as [Likely_benign]. Variant chr5-83542237-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.215 with no splicing effect.
• BS2: High AC in GnomAd at 405 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCAN	NM_004385.5	c.9234G>A	p.Glu3078=	synonymous_variant	8/15	ENST00000265077.8
VCAN-AS1	NR_136215.1	n.285-8064C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCAN	ENST00000265077.8	c.9234G>A	p.Glu3078=	synonymous_variant	8/15	1	NM_004385.5
VCAN-AS1	ENST00000513899.1	n.229-536C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 405 AN: 152168 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00407

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00297 AC: 742 AN: 249868 Hom.: 2 AF XY: 0.00320 AC XY: 432 AN XY: 135134

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00356

Gnomad FIN exome AF: 0.00136

Gnomad NFE exome AF: 0.00489

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00327 AC: 4784 AN: 1461472 Hom.: 12 Cov.: 34 AF XY: 0.00342 AC XY: 2488 AN XY: 727046

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00384

Gnomad4 FIN exome AF: 0.00151

Gnomad4 NFE exome AF: 0.00369

Gnomad4 OTH exome AF: 0.00275

GnomAD4 genome AF: 0.00266 AC: 405 AN: 152286 Hom.: 2 Cov.: 32 AF XY: 0.00238 AC XY: 177 AN XY: 74464

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00407

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00310 Hom.: 1

Bravo AF: 0.00284

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00498

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	VCAN: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Wagner syndrome Benign:2

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	- -

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	-0.41
Cadd	Benign	3.8
Dann	Benign	0.81

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: rs139453864; hg19: chr5-82838056; COSMIC: COSV105873542; COSMIC: COSV105873542;