NM_004385.5:c.9033C>A

Variant names:

• chr5-83542036-C-A
• rs16900532
• NM_004385.5:c.9033C>A

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.9033C>A​(p.Asn3011Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00896 in 1,610,478 control chromosomes in the GnomAD database, including 1,147 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. N3011D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.047 (573 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (574 hom.)
• Consequence: VCAN NM_004385.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.217
• Publications: 8 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=0.0012907684).
• BP6: Variant 5-83542036-C-A is Benign according to our data. Variant chr5-83542036-C-A is described in ClinVar as Benign. ClinVar VariationId is 259374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004385.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCAN	NM_004385.5	MANE Select	c.9033C>A	p.Asn3011Lys	missense	Exon 8 of 15	NP_004376.2
	VCAN	NM_001164097.2		c.6072C>A	p.Asn2024Lys	missense	Exon 7 of 14	NP_001157569.1	P13611-2
	VCAN	NM_001164098.2		c.4004-3501C>A		intron	N/A	NP_001157570.1	P13611-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCAN	ENST00000265077.8	TSL:1 MANE Select	c.9033C>A	p.Asn3011Lys	missense	Exon 8 of 15	ENSP00000265077.3	P13611-1
	VCAN	ENST00000343200.9	TSL:1	c.6072C>A	p.Asn2024Lys	missense	Exon 7 of 14	ENSP00000340062.5	P13611-2
	VCAN	ENST00000342785.8	TSL:1	c.4004-3501C>A		intron	N/A	ENSP00000342768.4	P13611-3

Frequencies

GnomAD3 genomes AF: 0.0466 AC: 7088 AN: 152064 Hom.: 572 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0349

GnomAD2 exomes AF: 0.0128 AC: 3194 AN: 249700 AF XY: 0.00909

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.00858

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000550

Gnomad OTH exome AF: 0.00775

GnomAD4 exome AF: 0.00503 AC: 7329 AN: 1458296 Hom.: 574 Cov.: 34 AF XY: 0.00428 AC XY: 3102 AN XY: 724860

African (AFR) AF: 0.175 AC: 5821 AN: 33284

American (AMR) AF: 0.00959 AC: 427 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 26020

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39622

South Asian (SAS) AF: 0.000488 AC: 42 AN: 86094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00940 AC: 54 AN: 5744

European-Non Finnish (NFE) AF: 0.000298 AC: 331 AN: 1109452

Other (OTH) AF: 0.0108 AC: 649 AN: 60230

GnomAD4 genome AF: 0.0467 AC: 7104 AN: 152182 Hom.: 573 Cov.: 32 AF XY: 0.0446 AC XY: 3315 AN XY: 74408

African (AFR) AF: 0.163 AC: 6746 AN: 41488

American (AMR) AF: 0.0158 AC: 242 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68004

Other (OTH) AF: 0.0346 AC: 73 AN: 2112

Alfa AF: 0.0177 Hom.: 510

Bravo AF: 0.0532

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.157 AC: 691

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0156 AC: 1896

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.000655

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Wagner disease (2)
-	-	1	not specified (1)
-	-	1	Vitreoretinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.86
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.22
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.028
Sift	Benign	0.046	D
Sift4G	Benign	0.53	T
Polyphen		0.0020	B
Vest4		0.17
MutPred		0.26		Gain of ubiquitination at N3011 (P = 0.0022)
MPC		0.096
ClinPred		0.00063	T
GERP RS		2.2
Varity_R		0.089
gMVP		0.19
Mutation Taster		=99/1	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: rs16900532; hg19: chr5-82837855;