5-83537550-A-G

Variant names:

• chr5-83537550-A-G
• rs309559
• NM_004385.5:c.4547A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004385.5(VCAN):​c.4547A>G​(p.Lys1516Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.486 in 1,613,366 control chromosomes in the GnomAD database, including 191,058 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1516E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.50 (19170 hom., cov: 31)
  • Exomes 𝑓: 0.48 (171888 hom.)
• Consequence: VCAN NM_004385.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.310
• Publications: 46 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.8598256E-5).
• BP6: Variant 5-83537550-A-G is Benign according to our data. Variant chr5-83537550-A-G is described in ClinVar as [Benign]. Clinvar id is 167820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5	c.4547A>G	p.Lys1516Arg	missense_variant	Exon 8 of 15	ENST00000265077.8	NP_004376.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8	c.4547A>G	p.Lys1516Arg	missense_variant	Exon 8 of 15	1	NM_004385.5	ENSP00000265077.3

Frequencies

GnomAD3 genomes AF: 0.501 AC: 76040 AN: 151706 Hom.: 19156 Cov.: 31

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.681

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.581

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.493

Gnomad OTH AF: 0.536

GnomAD2 exomes AF: 0.485 AC: 121133 AN: 249592 AF XY: 0.479

Gnomad AFR exome AF: 0.509

Gnomad AMR exome AF: 0.520

Gnomad ASJ exome AF: 0.575

Gnomad EAS exome AF: 0.399

Gnomad FIN exome AF: 0.513

Gnomad NFE exome AF: 0.499

Gnomad OTH exome AF: 0.496

GnomAD4 exome AF: 0.484 AC: 707325 AN: 1461542 Hom.: 171888 Cov.: 71 AF XY: 0.481 AC XY: 349777 AN XY: 727090

African (AFR) AF: 0.504 AC: 16858 AN: 33468

American (AMR) AF: 0.518 AC: 23135 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 15016 AN: 26128

East Asian (EAS) AF: 0.463 AC: 18377 AN: 39676

South Asian (SAS) AF: 0.389 AC: 33586 AN: 86256

European-Finnish (FIN) AF: 0.508 AC: 27111 AN: 53376

Middle Eastern (MID) AF: 0.503 AC: 2900 AN: 5768

European-Non Finnish (NFE) AF: 0.487 AC: 541333 AN: 1111848

Other (OTH) AF: 0.480 AC: 29009 AN: 60374

GnomAD4 genome AF: 0.501 AC: 76093 AN: 151824 Hom.: 19170 Cov.: 31 AF XY: 0.500 AC XY: 37108 AN XY: 74172

African (AFR) AF: 0.510 AC: 21122 AN: 41408

American (AMR) AF: 0.525 AC: 7992 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 2015 AN: 3466

East Asian (EAS) AF: 0.409 AC: 2108 AN: 5150

South Asian (SAS) AF: 0.392 AC: 1881 AN: 4800

European-Finnish (FIN) AF: 0.530 AC: 5579 AN: 10526

Middle Eastern (MID) AF: 0.500 AC: 146 AN: 292

European-Non Finnish (NFE) AF: 0.493 AC: 33497 AN: 67926

Other (OTH) AF: 0.537 AC: 1132 AN: 2108

Alfa AF: 0.497 Hom.: 58063

Bravo AF: 0.500

TwinsUK AF: 0.489 AC: 1815

ALSPAC AF: 0.485 AC: 1868

ESP6500AA AF: 0.505 AC: 2227

ESP6500EA AF: 0.495 AC: 4258

ExAC AF: 0.483 AC: 58635

Asia WGS AF: 0.412 AC: 1432 AN: 3478

EpiCase AF: 0.502

EpiControl AF: 0.503

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wagner syndrome Benign:3

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Vitreoretinopathy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.7
DANN	Benign	0.31
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.27	T;T;T
MetaRNN	Benign	0.000049	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N;.;.
PhyloP100		0.31
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.37	N;N;N
REVEL	Benign	0.085
Sift	Benign	0.11	T;T;D
Sift4G	Benign	0.48	T;T;T
Polyphen		0.011	B;B;.
Vest4		0.024
MPC		0.065
ClinPred		0.0080	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.056
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: rs309559; hg19: chr5-82833369; COSMIC: COSV54100091; COSMIC: COSV54100091;