NM_004385.5:c.8809G>T

Variant names:

• chr5-83541812-G-T
• rs160277
• NM_004385.5:c.8809G>T

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.8809G>T​(p.Asp2937Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,613,674 control chromosomes in the GnomAD database, including 117,940 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D2937D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.39 (11583 hom., cov: 32)
  • Exomes 𝑓: 0.38 (106357 hom.)
• Consequence: VCAN NM_004385.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.658
• 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=5.621314E-4).
• BP6: Variant 5-83541812-G-T is Benign according to our data. Variant chr5-83541812-G-T is described in ClinVar as Benign. ClinVar VariationId is 198802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5	c.8809G>T	p.Asp2937Tyr	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.8809G>T	p.Asp2937Tyr	missense_variant	Exon 8 of 15	1	NM_004385.5	ENSP00000265077.3

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58803 AN: 151792 Hom.: 11575 Cov.: 32

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.419

GnomAD2 exomes AF: 0.385 AC: 96445 AN: 250812 AF XY: 0.378

Gnomad AFR exome AF: 0.368

Gnomad AMR exome AF: 0.457

Gnomad ASJ exome AF: 0.478

Gnomad EAS exome AF: 0.343

Gnomad FIN exome AF: 0.389

Gnomad NFE exome AF: 0.392

Gnomad OTH exome AF: 0.395

GnomAD4 exome AF: 0.379 AC: 554703 AN: 1461764 Hom.: 106357 Cov.: 66 AF XY: 0.376 AC XY: 273768 AN XY: 727190

African (AFR) AF: 0.364 AC: 12191 AN: 33478

American (AMR) AF: 0.453 AC: 20270 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 12465 AN: 26134

East Asian (EAS) AF: 0.410 AC: 16283 AN: 39690

South Asian (SAS) AF: 0.275 AC: 23698 AN: 86256

European-Finnish (FIN) AF: 0.388 AC: 20689 AN: 53376

Middle Eastern (MID) AF: 0.418 AC: 2413 AN: 5766

European-Non Finnish (NFE) AF: 0.381 AC: 424130 AN: 1111950

Other (OTH) AF: 0.374 AC: 22564 AN: 60392

GnomAD4 genome AF: 0.387 AC: 58832 AN: 151910 Hom.: 11583 Cov.: 32 AF XY: 0.385 AC XY: 28603 AN XY: 74230

African (AFR) AF: 0.371 AC: 15374 AN: 41420

American (AMR) AF: 0.439 AC: 6694 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 1661 AN: 3468

East Asian (EAS) AF: 0.352 AC: 1809 AN: 5136

South Asian (SAS) AF: 0.271 AC: 1301 AN: 4806

European-Finnish (FIN) AF: 0.402 AC: 4237 AN: 10550

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26301 AN: 67956

Other (OTH) AF: 0.417 AC: 879 AN: 2106

Alfa AF: 0.388 Hom.: 55824

Bravo AF: 0.391

TwinsUK AF: 0.389 AC: 1443

ALSPAC AF: 0.378 AC: 1456

ESP6500AA AF: 0.369 AC: 1625

ESP6500EA AF: 0.399 AC: 3433

ExAC AF: 0.381 AC: 46242

Asia WGS AF: 0.286 AC: 992 AN: 3478

EpiCase AF: 0.399

EpiControl AF: 0.398

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wagner disease Benign:3

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

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

May 08, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19655167)

Vitreoretinopathy Benign:1

Mar 06, 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	0.092
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.79
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.49	T;T
MetaRNN	Benign	0.00056	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N;.
PhyloP100		0.66
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.094
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.021	D;D
Vest4		0.032
ClinPred		0.028	T
GERP RS		0.82
Varity_R		0.068
gMVP		0.18
Mutation Taster		=95/5	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: rs160277; hg19: chr5-82837631; COSMIC: COSV54100142; COSMIC: COSV54100142;