rs12332199

Positions:

• chr5-83490375-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004385.5(VCAN):​c.348T>C​(p.Thr116Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,613,948 control chromosomes in the GnomAD database, including 113,270 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12083 hom., cov: 32)
  • Exomes 𝑓: 0.37 (101187 hom.)
• Consequence: VCAN NM_004385.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.10

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-83490375-T-C is Benign according to our data. Variant chr5-83490375-T-C is described in ClinVar as [Benign]. Clinvar id is 259363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83490375-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCAN	NM_004385.5	c.348T>C	p.Thr116Thr	synonymous_variant	3/15	ENST00000265077.8	NP_004376.2
VCAN	NM_001164097.2	c.348T>C	p.Thr116Thr	synonymous_variant	3/14		NP_001157569.1
VCAN	NM_001164098.2	c.348T>C	p.Thr116Thr	synonymous_variant	3/14		NP_001157570.1
VCAN	NM_001126336.3	c.348T>C	p.Thr116Thr	synonymous_variant	3/13		NP_001119808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8	c.348T>C	p.Thr116Thr	synonymous_variant	3/15	1	NM_004385.5	ENSP00000265077.3

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59756 AN: 151976 Hom.: 12080 Cov.: 32

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.359

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.380

GnomAD3 exomes AF: 0.351 AC: 88073 AN: 251014 Hom.: 16226 AF XY: 0.343 AC XY: 46513 AN XY: 135654

Gnomad AFR exome AF: 0.476

Gnomad AMR exome AF: 0.404

Gnomad ASJ exome AF: 0.324

Gnomad EAS exome AF: 0.179

Gnomad SAS exome AF: 0.237

Gnomad FIN exome AF: 0.383

Gnomad NFE exome AF: 0.371

Gnomad OTH exome AF: 0.362

GnomAD4 exome AF: 0.368 AC: 537828 AN: 1461854 Hom.: 101187 Cov.: 64 AF XY: 0.363 AC XY: 264255 AN XY: 727230

Gnomad4 AFR exome AF: 0.486

Gnomad4 AMR exome AF: 0.404

Gnomad4 ASJ exome AF: 0.326

Gnomad4 EAS exome AF: 0.153

Gnomad4 SAS exome AF: 0.242

Gnomad4 FIN exome AF: 0.378

Gnomad4 NFE exome AF: 0.381

Gnomad4 OTH exome AF: 0.358

GnomAD4 genome AF: 0.393 AC: 59790 AN: 152094 Hom.: 12083 Cov.: 32 AF XY: 0.390 AC XY: 29012 AN XY: 74378

Gnomad4 AFR AF: 0.478

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.321

Gnomad4 EAS AF: 0.179

Gnomad4 SAS AF: 0.236

Gnomad4 FIN AF: 0.374

Gnomad4 NFE AF: 0.377

Gnomad4 OTH AF: 0.378

Alfa AF: 0.369 Hom.: 7924

Bravo AF: 0.401

Asia WGS AF: 0.242 AC: 845 AN: 3478

EpiCase AF: 0.369

EpiControl AF: 0.372

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	Genome-Nilou Lab	Dec 05, 2021	- -
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	GeneDx	Oct 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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	-0.85
CADD	Benign	2.8
DANN	Benign	0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs12332199; hg19: chr5-82786194; COSMIC: COSV54097214;