chr5-83493073-A-G

Variant names:

• chr5-83493073-A-G
• rs6452540
• NM_004385.5:c.446-473A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004385.5(VCAN):​c.446-473A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.878 in 152,262 control chromosomes in the GnomAD database, including 58,861 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.88 (58861 hom., cov: 33)
• Consequence: VCAN NM_004385.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00600
• Publications: 3 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 Gene-Disease associations (from GenCC):

• Wagner disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.938 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCAN	NM_004385.5	MANE Select	c.446-473A>G		intron	N/A	NP_004376.2
	VCAN	NM_001164097.2		c.446-473A>G		intron	N/A	NP_001157569.1
	VCAN	NM_001164098.2		c.446-473A>G		intron	N/A	NP_001157570.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCAN	ENST00000265077.8	TSL:1 MANE Select	c.446-473A>G		intron	N/A	ENSP00000265077.3
	VCAN	ENST00000343200.9	TSL:1	c.446-473A>G		intron	N/A	ENSP00000340062.5
	VCAN	ENST00000342785.8	TSL:1	c.446-473A>G		intron	N/A	ENSP00000342768.4

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133561 AN: 152144 Hom.: 58814 Cov.: 33

Gnomad AFR AF: 0.946

Gnomad AMI AF: 0.830

Gnomad AMR AF: 0.892

Gnomad ASJ AF: 0.838

Gnomad EAS AF: 0.915

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.839

Gnomad OTH AF: 0.873

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.878 AC: 133666 AN: 152262 Hom.: 58861 Cov.: 33 AF XY: 0.878 AC XY: 65373 AN XY: 74446

African (AFR) AF: 0.946 AC: 39314 AN: 41564

American (AMR) AF: 0.892 AC: 13639 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.838 AC: 2911 AN: 3472

East Asian (EAS) AF: 0.914 AC: 4730 AN: 5174

South Asian (SAS) AF: 0.833 AC: 4013 AN: 4820

European-Finnish (FIN) AF: 0.865 AC: 9177 AN: 10606

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.839 AC: 57050 AN: 68014

Other (OTH) AF: 0.870 AC: 1835 AN: 2110

Alfa AF: 0.856 Hom.: 70213

Bravo AF: 0.884

Asia WGS AF: 0.857 AC: 2979 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.3
DANN	Benign	0.61
PhyloP100		-0.0060
Mutation Taster		=100/0	polymorphism (auto)

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: rs6452540; hg19: chr5-82788892;