rs308365

chr5-83579981-C-T

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.9882C>T(p.Val3294=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.967 in 1,614,062 control chromosomes in the GnomAD database, including 755,470 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (72263 hom., cov: 33)
  • Exomes 𝑓: 0.97 (683207 hom.)
• Consequence: VCAN NM_004385.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.00006417
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.797

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 5-83579981-C-T is Benign according to our data. Variant chr5-83579981-C-T is described in ClinVar as [Benign]. Clinvar id is 259379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83579981-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.797 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCAN	NM_004385.5	c.9882C>T	p.Val3294=	splice_region_variant, synonymous_variant	14/15	ENST00000265077.8
VCAN	NM_001164097.2	c.6921C>T	p.Val2307=	splice_region_variant, synonymous_variant	13/14
VCAN	NM_001164098.2	c.4620C>T	p.Val1540=	splice_region_variant, synonymous_variant	13/14
VCAN	NM_001126336.3	c.1659C>T	p.Val553=	splice_region_variant, synonymous_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCAN	ENST00000265077.8	c.9882C>T	p.Val3294=	splice_region_variant, synonymous_variant	14/15	1	NM_004385.5
VCAN-AS1	ENST00000513899.1	n.228+1112G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.974 AC: 148231 AN: 152204 Hom.: 72201 Cov.: 33

Gnomad AFR AF: 0.993

Gnomad AMI AF: 0.946

Gnomad AMR AF: 0.975

Gnomad ASJ AF: 0.978

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.993

Gnomad FIN AF: 0.963

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.960

Gnomad OTH AF: 0.978

GnomAD3 exomes AF: 0.975 AC: 244924 AN: 251108 Hom.: 119477 AF XY: 0.975 AC XY: 132366 AN XY: 135744

Gnomad AFR exome AF: 0.993

Gnomad AMR exome AF: 0.989

Gnomad ASJ exome AF: 0.983

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.990

Gnomad FIN exome AF: 0.958

Gnomad NFE exome AF: 0.964

Gnomad OTH exome AF: 0.972

GnomAD4 exome AF: 0.967 AC: 1413159 AN: 1461740 Hom.: 683207 Cov.: 58 AF XY: 0.967 AC XY: 703263 AN XY: 727170

Gnomad4 AFR exome AF: 0.994

Gnomad4 AMR exome AF: 0.988

Gnomad4 ASJ exome AF: 0.983

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.991

Gnomad4 FIN exome AF: 0.957

Gnomad4 NFE exome AF: 0.962

Gnomad4 OTH exome AF: 0.971

GnomAD4 genome AF: 0.974 AC: 148352 AN: 152322 Hom.: 72263 Cov.: 33 AF XY: 0.975 AC XY: 72573 AN XY: 74472

Gnomad4 AFR AF: 0.993

Gnomad4 AMR AF: 0.975

Gnomad4 ASJ AF: 0.978

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.993

Gnomad4 FIN AF: 0.963

Gnomad4 NFE AF: 0.960

Gnomad4 OTH AF: 0.978

Alfa AF: 0.967 Hom.: 149673

Bravo AF: 0.976

Asia WGS AF: 0.997 AC: 3466 AN: 3478

EpiCase AF: 0.964

EpiControl AF: 0.966

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wagner syndrome Benign:5

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	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 19, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

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	-0.49
Cadd	Benign	9.6
Dann	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.014
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: rs308365; hg19: chr5-82875800;