NM_004385.5:c.6721_6723delAGAinsTCC

Variant names:

• chr5-83539724-AGA-TCC
• NM_004385.5:c.6721_6723delAGAinsTCC
• VCAN p.Arg2241Ser

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_004385.5(VCAN):c.6721_6723delAGAinsTCC (p.Arg2241Ser) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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: 0.173
• 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: Uncertain_significance. The variant received 2 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.

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.6721_6723delAGAinsTCC p.Arg2241Ser	missense	N/A	Prot: NP_004376.2
	VCAN NM_001164097.2		c.3760_3762delAGAinsTCC p.Arg1254Ser	missense	N/A	Prot: NP_001157569.1 UniProt:
	VCAN NM_001164098.2		c.4004-5813_4004-5811delAGAinsTCC	intron	Intron 7 of 13	Prot: NP_001157570.1 UniProt:

VCAN NM_004385.5

MANE Select

HGVSc / HGVSpc.6721_6723delAGAinsTCCp.Arg2241Ser

Exon rankN/A

missense

Prot: NP_004376.2

VCAN NM_001164097.2

HGVSc / HGVSpc.3760_3762delAGAinsTCCp.Arg1254Ser

Exon rankN/A

missense

Prot: NP_001157569.1UniProt: P13611-2

VCAN NM_001164098.2

HGVSc / HGVSpc.4004-5813_4004-5811delAGAinsTCC

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.6721_6723delAGAinsTCC p.Arg2241Ser	missense	N/A	Prot: ENSP00000265077.3 UniProt:
	VCAN ENST00000343200.9	TSL:1	c.3760_3762delAGAinsTCC p.Arg1254Ser	missense	N/A	Prot: ENSP00000340062.5 UniProt:
	VCAN ENST00000342785.8	TSL:1	c.4004-5813_4004-5811delAGAinsTCC	intron	Intron 7 of 13	Prot: ENSP00000342768.4 UniProt:

VCAN ENST00000265077.8

TSL:1MANE Select

HGVSc / HGVSpc.6721_6723delAGAinsTCCp.Arg2241Ser

Exon rankN/A

missense

Prot: ENSP00000265077.3UniProt: P13611-1

VCAN ENST00000343200.9

TSL:1

HGVSc / HGVSpc.3760_3762delAGAinsTCCp.Arg1254Ser

Exon rankN/A

missense

Prot: ENSP00000340062.5UniProt: P13611-2

VCAN ENST00000342785.8

TSL:1

HGVSc / HGVSpc.4004-5813_4004-5811delAGAinsTCC

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

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.17

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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