5-83490420-C-T

Position:

• chr5-83490420-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.393C>T​(p.Asp131Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,104 control chromosomes in the GnomAD database, including 542 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (73 hom., cov: 32)
  • Exomes 𝑓: 0.011 (469 hom.)
• Consequence: VCAN NM_004385.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.39

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=-0.71).
• BP6: Variant 5-83490420-C-T is Benign according to our data. Variant chr5-83490420-C-T is described in ClinVar as [Benign]. Clinvar id is 259364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83490420-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.064 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCAN	NM_004385.5	c.393C>T	p.Asp131Asp	synonymous_variant	3/15	ENST00000265077.8	NP_004376.2
VCAN	NM_001164097.2	c.393C>T	p.Asp131Asp	synonymous_variant	3/14		NP_001157569.1
VCAN	NM_001164098.2	c.393C>T	p.Asp131Asp	synonymous_variant	3/14		NP_001157570.1
VCAN	NM_001126336.3	c.393C>T	p.Asp131Asp	synonymous_variant	3/13		NP_001119808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8	c.393C>T	p.Asp131Asp	synonymous_variant	3/15	1	NM_004385.5	ENSP00000265077.3

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 3003 AN: 152108 Hom.: 73 Cov.: 32

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.0697

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.0292

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00498

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0289 AC: 7246 AN: 251108 Hom.: 318 AF XY: 0.0247 AC XY: 3349 AN XY: 135704

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.00676

Gnomad EAS exome AF: 0.0737

Gnomad SAS exome AF: 0.00441

Gnomad FIN exome AF: 0.0334

Gnomad NFE exome AF: 0.00687

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0114 AC: 16608 AN: 1461878 Hom.: 469 Cov.: 33 AF XY: 0.0108 AC XY: 7857 AN XY: 727240

Gnomad4 AFR exome AF: 0.0205

Gnomad4 AMR exome AF: 0.100

Gnomad4 ASJ exome AF: 0.00888

Gnomad4 EAS exome AF: 0.0719

Gnomad4 SAS exome AF: 0.00415

Gnomad4 FIN exome AF: 0.0311

Gnomad4 NFE exome AF: 0.00475

Gnomad4 OTH exome AF: 0.0156

GnomAD4 genome AF: 0.0198 AC: 3008 AN: 152226 Hom.: 73 Cov.: 32 AF XY: 0.0217 AC XY: 1618 AN XY: 74438

Gnomad4 AFR AF: 0.0209

Gnomad4 AMR AF: 0.0649

Gnomad4 ASJ AF: 0.0132

Gnomad4 EAS AF: 0.0699

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.0292

Gnomad4 NFE AF: 0.00498

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.00807 Hom.: 4

Bravo AF: 0.0242

Asia WGS AF: 0.0440 AC: 151 AN: 3478

EpiCase AF: 0.00589

EpiControl AF: 0.00818

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wagner syndrome Benign:2

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	- -

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	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 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	-0.71
CADD	Benign	0.57
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs35042106; hg19: chr5-82786239; COSMIC: COSV54097227;