5-83537009-C-T

Position:

• chr5-83537009-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004385.5(VCAN):​c.4006C>T​(p.Arg1336Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCAN NM_004385.5 stop_gained, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.49

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-83537009-C-T is Pathogenic according to our data. Variant chr5-83537009-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1459411.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCAN	NM_004385.5	c.4006C>T	p.Arg1336Ter	stop_gained, splice_region_variant	8/15	ENST00000265077.8	NP_004376.2
VCAN-AS1	NR_136215.1	n.285-2836G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8	c.4006C>T	p.Arg1336Ter	stop_gained, splice_region_variant	8/15	1	NM_004385.5	ENSP00000265077

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1459411). This variant has not been reported in the literature in individuals affected with VCAN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1336*) in the VCAN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VCAN are known to be pathogenic (PMID: 26720455). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A;A;D;D;D
Vest4		0.92
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs928940812; hg19: chr5-82832828; COSMIC: COSV104594789; COSMIC: COSV104594789;