5-83539726-A-G

Variant names:

• chr5-83539726-A-G
• rs160279
• NM_004385.5:c.6723A>G
• VCAN p.Arg2241Arg

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -17 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_StrongBP7

The NM_004385.5(VCAN):c.6723A>G (p.Arg2241Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.485 (AC=782,988) in the gnomAD database across 1,613,372 control chromosomes, including 190,803 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.516. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19064 hom., cov: 32)
  • Exomes 𝑓: 0.48 (171739 hom.)
• Consequence: VCAN NM_004385.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.423
• Publications: 24 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: ClinGen, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia

VCAN-AS1 (HGNC:40163): ()

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.5163 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	VCAN NM_004385.5	MANE Select	c.6723A>G p.Arg2241Arg	synonymous	Exon 8 of 15	Prot: NP_004376.2
	VCAN NM_001164097.2		c.3762A>G p.Arg1254Arg	synonymous	Exon 7 of 14	Prot: NP_001157569.1 UniProt:
	VCAN NM_001164098.2		c.4004-5811A>G	intron	Intron 7 of 13	Prot: NP_001157570.1 UniProt:

VCAN NM_004385.5

MANE Select

HGVSc / HGVSpc.6723A>Gp.Arg2241Arg

Exon rankExon 8 of 15

synonymous

Prot: NP_004376.2

VCAN NM_001164097.2

HGVSc / HGVSpc.3762A>Gp.Arg1254Arg

Exon rankExon 7 of 14

synonymous

Prot: NP_001157569.1UniProt: P13611-2

VCAN NM_001164098.2

HGVSc / HGVSpc.4004-5811A>G

Exon rankIntron 7 of 13

intron

Prot: NP_001157570.1UniProt: P13611-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	VCAN ENST00000265077.8	TSL:1MANE Select	c.6723A>G p.Arg2241Arg	synonymous	Exon 8 of 15	Prot: ENSP00000265077.3 UniProt:
	VCAN ENST00000343200.9	TSL:1	c.3762A>G p.Arg1254Arg	synonymous	Exon 7 of 14	Prot: ENSP00000340062.5 UniProt:
	VCAN ENST00000342785.8	TSL:1	c.4004-5811A>G	intron	Intron 7 of 13	Prot: ENSP00000342768.4 UniProt:

VCAN ENST00000265077.8

TSL:1MANE Select

HGVSc / HGVSpc.6723A>Gp.Arg2241Arg

Exon rankExon 8 of 15

synonymous

Prot: ENSP00000265077.3UniProt: P13611-1

VCAN ENST00000343200.9

TSL:1

HGVSc / HGVSpc.3762A>Gp.Arg1254Arg

Exon rankExon 7 of 14

synonymous

Prot: ENSP00000340062.5UniProt: P13611-2

VCAN ENST00000342785.8

TSL:1

HGVSc / HGVSpc.4004-5811A>G

Exon rankIntron 7 of 13

intron

Prot: ENSP00000342768.4UniProt: P13611-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.500	AC:75894	Hom:19051	AN:151866	Cov:32
GnomAD2 exomes	AF: 0.485	AC:121044	Hom:	AN:249592	Cov:
GnomAD4 exome	AF: 0.484	AC:707047	Hom:171739	AN:1461386	Cov:72
GnomAD4 genome	AF: 0.500	AC:75941	Hom:19064	AN:151986	Cov:32
TOPMed (Bravo)	AF: 0.499	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.500	AC:69314	Hom:17588	AN:138624	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.535	AC:1253	Hom:333	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.377	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.507	AC:152	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.497	AC:6464	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.411	AC:1426	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.420	AC:3039	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.491	AC:988	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.518	AC:63659	Hom:16531	AN:122784	Cov:
Turkish Variome	AF: 0.465	AC:3113	Hom:748	AN:6698	Cov:
UK10K	AF: 0.487	AC:3680	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.369	AC:3307	Hom:609	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.490 *	5435	11100	0.488 *	8591	17600
BipEx(Bipolar disorder (including schizoaffective))	0.493	14007	28420	0.494	14246	28844
Epi25(Epilepsy)	0.488	20481	41958	0.491	32829	66886
SCHEMA(Schizophrenia)	0.463	61677	133088	0.472	102708	217496

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	8.8
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.1
DANN	Benign	0.62
GPN-Star LLR	N/A	-2.1
GPN-Star score	N/A	2.1
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.42

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs160279;

hg19: chr5-82835545;

COSMIC: COSV54100118;

COSMIC: COSV54100118;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar