rs11746859

Variant names:

• chr5-83474739-A-G
• rs11746859
• NM_004385.5:c.-7+2716A>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.-7+2716A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 152,162 control chromosomes in the GnomAD database, including 11,904 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 0.39 (11904 hom., cov: 34)
• Consequence: VCAN NM_004385.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.84
• Publications: 6 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5	c.-7+2716A>G		intron_variant	Intron 1 of 14	ENST00000265077.8	NP_004376.2
VCAN	NM_001164097.2	c.-7+2716A>G		intron_variant	Intron 1 of 13		NP_001157569.1
VCAN	NM_001164098.2	c.-7+2716A>G		intron_variant	Intron 1 of 13		NP_001157570.1
VCAN	NM_001126336.3	c.-7+2716A>G		intron_variant	Intron 1 of 12		NP_001119808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8	c.-7+2716A>G		intron_variant	Intron 1 of 14	1	NM_004385.5	ENSP00000265077.3

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59261 AN: 152044 Hom.: 11912 Cov.: 34

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.406

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

GnomAD4 genome AF: 0.389 AC: 59243 AN: 152162 Hom.: 11904 Cov.: 34 AF XY: 0.385 AC XY: 28662 AN XY: 74390

African (AFR) AF: 0.295 AC: 12263 AN: 41504

American (AMR) AF: 0.357 AC: 5460 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1700 AN: 3472

East Asian (EAS) AF: 0.311 AC: 1604 AN: 5158

South Asian (SAS) AF: 0.335 AC: 1615 AN: 4820

European-Finnish (FIN) AF: 0.400 AC: 4242 AN: 10602

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.454 AC: 30881 AN: 67986

Other (OTH) AF: 0.404 AC: 852 AN: 2110

Alfa AF: 0.435 Hom.: 23131

Bravo AF: 0.385

Asia WGS AF: 0.311 AC: 1084 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.6
DANN	Benign	0.72
PhyloP100		-1.8
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: rs11746859; hg19: chr5-82770558;