rs113659987

Variant names:

• chr5-83539126-C-G
• rs113659987
• NM_004385.5:c.6123C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-83539126-C-G
• chr5-83539126-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004385.5(VCAN):​c.6123C>G​(p.Ile2041Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I2041I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCAN NM_004385.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.515
• 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-AS1 (HGNC:40163): (VCAN antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16201076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5	c.6123C>G	p.Ile2041Met	missense_variant	Exon 8 of 15	ENST00000265077.8	NP_004376.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8	c.6123C>G	p.Ile2041Met	missense_variant	Exon 8 of 15	1	NM_004385.5	ENSP00000265077.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 79

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2041 of the VCAN protein (p.Ile2041Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VCAN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1719554). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;.;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.65	T;T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.7	L;.;.
PhyloP100		0.52
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.58	N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0070	D;D;D
Sift4G	Benign	0.26	T;T;T
Polyphen		0.94	P;D;.
Vest4		0.17
MutPred		0.28		Loss of stability (P = 0.024);.;.;
MVP		0.47
MPC		0.31
ClinPred		0.45	T
GERP RS		4.2
Varity_R		0.076
gMVP		0.098
Mutation Taster		=96/4	polymorphism

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: rs113659987; hg19: chr5-82834945;