5-83542270-T-C

Variant names:

• chr5-83542270-T-C
• rs397515437
• NM_004385.5:c.9265+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PS3 PM2 PP5_Moderate

The NM_004385.5(VCAN):​c.9265+2T>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV004332853: RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. PMID:16636652, PMID:19901218, PMID:22739342".

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCAN NM_004385.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9847
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.26
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.51633793 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004332853: RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. PMID:16636652, PMID:19901218, PMID:22739342
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-83542270-T-C is Pathogenic according to our data. Variant chr5-83542270-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2765729.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004385.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCAN	NM_004385.5	MANE Select	c.9265+2T>C		splice_donor intron	N/A	NP_004376.2
	VCAN	NM_001164097.2		c.6304+2T>C		splice_donor intron	N/A	NP_001157569.1	P13611-2
	VCAN	NM_001164098.2		c.4004-3267T>C		intron	N/A	NP_001157570.1	P13611-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCAN	ENST00000265077.8	TSL:1 MANE Select	c.9265+2T>C		splice_donor intron	N/A	ENSP00000265077.3	P13611-1
	VCAN	ENST00000343200.9	TSL:1	c.6304+2T>C		splice_donor intron	N/A	ENSP00000340062.5	P13611-2
	VCAN	ENST00000342785.8	TSL:1	c.4004-3267T>C		intron	N/A	ENSP00000342768.4	P13611-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		5.3
GERP RS		5.9
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		Position offset: -2

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

Other links and lift over

dbSNP: rs397515437; hg19: chr5-82838089;