5-83537619-C-G

Variant names:

• chr5-83537619-C-G
• NM_004385.5:c.4616C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004385.5(VCAN):​c.4616C>G​(p.Pro1539Arg) 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. 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)
• Consequence: VCAN NM_004385.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0290

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05282089).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5	c.4616C>G	p.Pro1539Arg	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.4616C>G	p.Pro1539Arg	missense_variant	Exon 8 of 15	1	NM_004385.5	ENSP00000265077.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 77

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4616C>G (p.P1539R) alteration is located in exon 8 (coding exon 7) of the VCAN gene. This alteration results from a C to G substitution at nucleotide position 4616, causing the proline (P) at amino acid position 1539 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	10
DANN	Benign	0.90
DEOGEN2	Benign	0.16	T;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D;D;D
Sift4G	Benign	0.24	T;T;T
Polyphen		0.090	B;B;.
Vest4		0.14
MutPred		0.15		Loss of glycosylation at S1541 (P = 0.0676);.;.;
MVP		0.32
MPC		0.14
ClinPred		0.065	T
GERP RS		0.78
Varity_R		0.035
gMVP		0.053

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: chr5-82833438;