rs12332199

Variant names:

• chr5-83490375-T-C
• rs12332199
• NM_004385.5:c.348T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 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 -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 VariationId is 259363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.473 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.348T>C	p.Thr116Thr	synonymous	Exon 3 of 15	NP_004376.2
	VCAN	NM_001164097.2		c.348T>C	p.Thr116Thr	synonymous	Exon 3 of 14	NP_001157569.1	P13611-2
	VCAN	NM_001164098.2		c.348T>C	p.Thr116Thr	synonymous	Exon 3 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.348T>C	p.Thr116Thr	synonymous	Exon 3 of 15	ENSP00000265077.3	P13611-1
	VCAN	ENST00000343200.9	TSL:1	c.348T>C	p.Thr116Thr	synonymous	Exon 3 of 14	ENSP00000340062.5	P13611-2
	VCAN	ENST00000342785.8	TSL:1	c.348T>C	p.Thr116Thr	synonymous	Exon 3 of 14	ENSP00000342768.4	P13611-3

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

GnomAD2 exomes AF: 0.351 AC: 88073 AN: 251014 AF XY: 0.343

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 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

African (AFR) AF: 0.486 AC: 16272 AN: 33480

American (AMR) AF: 0.404 AC: 18087 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 8528 AN: 26134

East Asian (EAS) AF: 0.153 AC: 6093 AN: 39698

South Asian (SAS) AF: 0.242 AC: 20860 AN: 86258

European-Finnish (FIN) AF: 0.378 AC: 20163 AN: 53402

Middle Eastern (MID) AF: 0.356 AC: 2051 AN: 5768

European-Non Finnish (NFE) AF: 0.381 AC: 424124 AN: 1111996

Other (OTH) AF: 0.358 AC: 21650 AN: 60396

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

African (AFR) AF: 0.478 AC: 19836 AN: 41464

American (AMR) AF: 0.388 AC: 5930 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1112 AN: 3468

East Asian (EAS) AF: 0.179 AC: 927 AN: 5176

South Asian (SAS) AF: 0.236 AC: 1139 AN: 4826

European-Finnish (FIN) AF: 0.374 AC: 3960 AN: 10576

Middle Eastern (MID) AF: 0.359 AC: 104 AN: 290

European-Non Finnish (NFE) AF: 0.377 AC: 25616 AN: 67982

Other (OTH) AF: 0.378 AC: 797 AN: 2110

Alfa AF: 0.369 Hom.: 8536

Bravo AF: 0.401

Asia WGS AF: 0.242 AC: 845 AN: 3478

EpiCase AF: 0.369

EpiControl AF: 0.372

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	-0.85
CADD	Benign	2.8
DANN	Benign	0.23
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs12332199; hg19: chr5-82786194; COSMIC: COSV54097214;