chr5-83539726-A-C

Variant names:

• chr5-83539726-A-C
• rs160279
• NM_004385.5:c.6723A>C
• VCAN p.Arg2241Ser

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_004385.5(VCAN):c.6723A>C (p.Arg2241Ser) variant causes a missense 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 (REVEL) 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. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R2241= (synonymous): Benign (ClinVar VariationId 198797, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCAN NM_004385.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.423
• Publications: 2 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: Uncertain_significance. The variant received 0 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 (Moderate).

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>C p.Arg2241Ser	missense	Exon 8 of 15	Prot: NP_004376.2
	VCAN NM_001164097.2		c.3762A>C p.Arg1254Ser	missense	Exon 7 of 14	Prot: NP_001157569.1 UniProt:
	VCAN NM_001164098.2		c.4004-5811A>C	intron	Intron 7 of 13	Prot: NP_001157570.1 UniProt:

VCAN NM_004385.5

MANE Select

HGVSc / HGVSpc.6723A>Cp.Arg2241Ser

Exon rankExon 8 of 15

missense

Prot: NP_004376.2

VCAN NM_001164097.2

HGVSc / HGVSpc.3762A>Cp.Arg1254Ser

Exon rankExon 7 of 14

missense

Prot: NP_001157569.1UniProt: P13611-2

VCAN NM_001164098.2

HGVSc / HGVSpc.4004-5811A>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.6723A>C p.Arg2241Ser	missense	Exon 8 of 15	Prot: ENSP00000265077.3 UniProt:
	VCAN ENST00000343200.9	TSL:1	c.3762A>C p.Arg1254Ser	missense	Exon 7 of 14	Prot: ENSP00000340062.5 UniProt:
	VCAN ENST00000342785.8	TSL:1	c.4004-5811A>C	intron	Intron 7 of 13	Prot: ENSP00000342768.4 UniProt:

VCAN ENST00000265077.8

TSL:1MANE Select

HGVSc / HGVSpc.6723A>Cp.Arg2241Ser

Exon rankExon 8 of 15

missense

Prot: ENSP00000265077.3UniProt: P13611-1

VCAN ENST00000343200.9

TSL:1

HGVSc / HGVSpc.3762A>Cp.Arg1254Ser

Exon rankExon 7 of 14

missense

Prot: ENSP00000340062.5UniProt: P13611-2

VCAN ENST00000342785.8

TSL:1

HGVSc / HGVSpc.4004-5811A>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:72
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	Uncertain	11
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.8
DANN	Benign	0.89
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.066	N
FuncVEP CTI	Benign	0.0013
GPN-Star LLR	N/A	-3.0
GPN-Star score	N/A	3.0
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.98	T
Mutation Taster	N/A	89/11	polymorphism
MutationAssessor	Benign	1.5	L
PhyloP100	Benign	-0.42
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.029
Sift	Benign	0.096	T
Sift4G	Benign	0.44	T
Varity_R	N/A	0.077
VESM-3B	Benign	-0.99

Showing 27 of 27 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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar