rs695103

chr5-83545657-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004385.5(VCAN):c.9379+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,608,182 control chromosomes in the GnomAD database, including 15,074 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1115 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13959 hom.)
• Consequence: VCAN NM_004385.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001425
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.685

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-83545657-T-C is Benign according to our data. Variant chr5-83545657-T-C is described in ClinVar as [Benign]. Clinvar id is 259377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83545657-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCAN	NM_004385.5	c.9379+7T>C		splice_region_variant, intron_variant		ENST00000265077.8
VCAN-AS1	NR_136215.1	n.285-11484A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCAN	ENST00000265077.8	c.9379+7T>C		splice_region_variant, intron_variant		1	NM_004385.5
VCAN-AS1	ENST00000513899.1	n.229-3956A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16105 AN: 152120 Hom.: 1113 Cov.: 33

Gnomad AFR AF: 0.0529

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0731

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.115

GnomAD3 exomes AF: 0.139 AC: 34968 AN: 251054 Hom.: 3330 AF XY: 0.152 AC XY: 20670 AN XY: 135660

Gnomad AFR exome AF: 0.0504

Gnomad AMR exome AF: 0.0572

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.232

Gnomad SAS exome AF: 0.318

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.114

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.126 AC: 183889 AN: 1455944 Hom.: 13959 Cov.: 29 AF XY: 0.133 AC XY: 96256 AN XY: 724804

Gnomad4 AFR exome AF: 0.0523

Gnomad4 AMR exome AF: 0.0613

Gnomad4 ASJ exome AF: 0.136

Gnomad4 EAS exome AF: 0.196

Gnomad4 SAS exome AF: 0.314

Gnomad4 FIN exome AF: 0.140

Gnomad4 NFE exome AF: 0.112

Gnomad4 OTH exome AF: 0.138

GnomAD4 genome AF: 0.106 AC: 16116 AN: 152238 Hom.: 1115 Cov.: 33 AF XY: 0.113 AC XY: 8426 AN XY: 74426

Gnomad4 AFR AF: 0.0529

Gnomad4 AMR AF: 0.0732

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.226

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.139

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.114

Alfa AF: 0.116 Hom.: 1723

Bravo AF: 0.0935

Asia WGS AF: 0.234 AC: 811 AN: 3476

EpiCase AF: 0.120

EpiControl AF: 0.120

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wagner syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Vitreoretinopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	6.8
Dann	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.11		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: rs695103; hg19: chr5-82841476; COSMIC: COSV54100178;