5-83483567-G-A

Variant names:

• chr5-83483567-G-A
• NM_004385.5:c.49G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004385.5(VCAN):​c.49G>A​(p.Val17Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: VCAN NM_004385.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.064563185).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5	c.49G>A	p.Val17Ile	missense_variant	Exon 2 of 15	ENST00000265077.8	NP_004376.2
VCAN	NM_001164097.2	c.49G>A	p.Val17Ile	missense_variant	Exon 2 of 14		NP_001157569.1
VCAN	NM_001164098.2	c.49G>A	p.Val17Ile	missense_variant	Exon 2 of 14		NP_001157570.1
VCAN	NM_001126336.3	c.49G>A	p.Val17Ile	missense_variant	Exon 2 of 13		NP_001119808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8	c.49G>A	p.Val17Ile	missense_variant	Exon 2 of 15	1	NM_004385.5	ENSP00000265077.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461204 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726928

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 17 of the VCAN protein (p.Val17Ile). 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. 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 tolerated. 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	0.094
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.20
DEOGEN2	Benign	0.093	T;.;.;.;T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.58	T;T;T;T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.065	T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.0	L;L;L;.;.;L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.21	N;N;N;N;N;N
REVEL	Benign	0.059
Sift	Benign	0.48	T;T;T;T;T;T
Sift4G	Benign	0.72	T;T;T;T;T;T
Polyphen		0.0030	B;B;B;.;B;B
Vest4		0.15
MutPred		0.27		Loss of MoRF binding (P = 0.1599);Loss of MoRF binding (P = 0.1599);Loss of MoRF binding (P = 0.1599);Loss of MoRF binding (P = 0.1599);Loss of MoRF binding (P = 0.1599);Loss of MoRF binding (P = 0.1599);
MVP		0.32
MPC		0.066
ClinPred		0.047	T
GERP RS		2.5
Varity_R		0.017
gMVP		0.22

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-82779386;