rs695103

Positions:

chr5-83545657-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Variant links:

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 links:

VCAN-AS1 (HGNC:40163): (VCAN antisense RNA 1)

VCAN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
VCAN	NM_004385.5 linkuse as main transcript	c.9379+7T>C		splice_region_variant, intron_variant		ENST00000265077.8	NP_004376.2
VCAN-AS1	NR_136215.1 linkuse as main transcript	n.285-11484A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8 linkuse as main transcript	c.9379+7T>C		splice_region_variant, intron_variant		1	NM_004385.5	ENSP00000265077		P13611-1
VCAN-AS1	ENST00000513899.1 linkuse as main transcript	n.229-3956A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16105

AN:

152120

Hom.:

1113

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.133

AC XY:

96256

AN XY:

724804

show subpopulations

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.:

AF XY:

0.113

AC XY:

8426

AN XY:

74426

show subpopulations

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

LINK: link

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2021	- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over