NM_004385.5:c.6721A>C

Variant names:

• chr5-83539724-A-C
• NM_004385.5:c.6721A>C
• VCAN p.Arg2241Arg

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_StrongBP7

The NM_004385.5(VCAN):c.6721A>C (p.Arg2241Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCAN NM_004385.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.173
• Publications: 0 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: Likely_benign. The variant received -3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	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).
	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).

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.6721A>C p.Arg2241Arg	synonymous	Exon 8 of 15	Prot: NP_004376.2
	VCAN NM_001164097.2		c.3760A>C p.Arg1254Arg	synonymous	Exon 7 of 14	Prot: NP_001157569.1 UniProt:
	VCAN NM_001164098.2		c.4004-5813A>C	intron	Intron 7 of 13	Prot: NP_001157570.1 UniProt:

VCAN NM_004385.5

MANE Select

HGVSc / HGVSpc.6721A>Cp.Arg2241Arg

Exon rankExon 8 of 15

synonymous

Prot: NP_004376.2

VCAN NM_001164097.2

HGVSc / HGVSpc.3760A>Cp.Arg1254Arg

Exon rankExon 7 of 14

synonymous

Prot: NP_001157569.1UniProt: P13611-2

VCAN NM_001164098.2

HGVSc / HGVSpc.4004-5813A>C

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.6721A>C p.Arg2241Arg	synonymous	Exon 8 of 15	Prot: ENSP00000265077.3 UniProt:
	VCAN ENST00000343200.9	TSL:1	c.3760A>C p.Arg1254Arg	synonymous	Exon 7 of 14	Prot: ENSP00000340062.5 UniProt:
	VCAN ENST00000342785.8	TSL:1	c.4004-5813A>C	intron	Intron 7 of 13	Prot: ENSP00000342768.4 UniProt:

VCAN ENST00000265077.8

TSL:1MANE Select

HGVSc / HGVSpc.6721A>Cp.Arg2241Arg

Exon rankExon 8 of 15

synonymous

Prot: ENSP00000265077.3UniProt: P13611-1

VCAN ENST00000343200.9

TSL:1

HGVSc / HGVSpc.3760A>Cp.Arg1254Arg

Exon rankExon 7 of 14

synonymous

Prot: ENSP00000340062.5UniProt: P13611-2

VCAN ENST00000342785.8

TSL:1

HGVSc / HGVSpc.4004-5813A>C

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:79
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	6.5
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.4
DANN	Benign	0.69
GPN-Star LLR	N/A	-2.8
GPN-Star score	N/A	2.8
PhyloP100	Benign	0.17

Showing 7 of 7 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

hg19: chr5-82835543;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar