rs4470745

Variant names:

• chr5-83493828-A-G
• rs4470745
• NM_004385.5:c.645A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004385.5(VCAN):​c.645A>G​(p.Val215Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,613,894 control chromosomes in the GnomAD database, including 118,135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8925 hom., cov: 32)
  • Exomes 𝑓: 0.38 (109210 hom.)
• Consequence: VCAN NM_004385.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.282
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• Wagner disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 5-83493828-A-G is Benign according to our data. Variant chr5-83493828-A-G is described in ClinVar as Benign. ClinVar VariationId is 259373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.282 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004385.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCAN	NM_004385.5	MANE Select	c.645A>G	p.Val215Val	synonymous	Exon 5 of 15	NP_004376.2
	VCAN	NM_001164097.2		c.645A>G	p.Val215Val	synonymous	Exon 5 of 14	NP_001157569.1	P13611-2
	VCAN	NM_001164098.2		c.645A>G	p.Val215Val	synonymous	Exon 5 of 14	NP_001157570.1	P13611-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCAN	ENST00000265077.8	TSL:1 MANE Select	c.645A>G	p.Val215Val	synonymous	Exon 5 of 15	ENSP00000265077.3	P13611-1
	VCAN	ENST00000343200.9	TSL:1	c.645A>G	p.Val215Val	synonymous	Exon 5 of 14	ENSP00000340062.5	P13611-2
	VCAN	ENST00000342785.8	TSL:1	c.645A>G	p.Val215Val	synonymous	Exon 5 of 14	ENSP00000342768.4	P13611-3

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50285 AN: 151934 Hom.: 8930 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.0792

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.320

GnomAD2 exomes AF: 0.322 AC: 80932 AN: 251278 AF XY: 0.325

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.270

Gnomad ASJ exome AF: 0.364

Gnomad EAS exome AF: 0.0686

Gnomad FIN exome AF: 0.376

Gnomad NFE exome AF: 0.398

Gnomad OTH exome AF: 0.356

GnomAD4 exome AF: 0.379 AC: 554125 AN: 1461842 Hom.: 109210 Cov.: 63 AF XY: 0.376 AC XY: 273369 AN XY: 727224

African (AFR) AF: 0.240 AC: 8036 AN: 33480

American (AMR) AF: 0.279 AC: 12481 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 9446 AN: 26134

East Asian (EAS) AF: 0.0545 AC: 2165 AN: 39698

South Asian (SAS) AF: 0.244 AC: 21072 AN: 86256

European-Finnish (FIN) AF: 0.375 AC: 20012 AN: 53416

Middle Eastern (MID) AF: 0.331 AC: 1907 AN: 5768

European-Non Finnish (NFE) AF: 0.411 AC: 457570 AN: 1111978

Other (OTH) AF: 0.355 AC: 21436 AN: 60390

GnomAD4 genome AF: 0.331 AC: 50274 AN: 152052 Hom.: 8925 Cov.: 32 AF XY: 0.326 AC XY: 24212 AN XY: 74310

African (AFR) AF: 0.243 AC: 10062 AN: 41468

American (AMR) AF: 0.306 AC: 4676 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1227 AN: 3472

East Asian (EAS) AF: 0.0794 AC: 411 AN: 5178

South Asian (SAS) AF: 0.234 AC: 1127 AN: 4822

European-Finnish (FIN) AF: 0.373 AC: 3934 AN: 10552

Middle Eastern (MID) AF: 0.322 AC: 94 AN: 292

European-Non Finnish (NFE) AF: 0.407 AC: 27669 AN: 67966

Other (OTH) AF: 0.318 AC: 673 AN: 2114

Alfa AF: 0.382 Hom.: 21378

Bravo AF: 0.322

Asia WGS AF: 0.181 AC: 631 AN: 3478

EpiCase AF: 0.403

EpiControl AF: 0.400

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Wagner disease (3)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Vitreoretinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.8
DANN	Benign	0.75
PhyloP100		0.28
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4470745; hg19: chr5-82789647; COSMIC: COSV54104482;