5-83483574-A-G

Variant names:

• chr5-83483574-A-G
• rs781014698
• NM_004385.5:c.56A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004385.5(VCAN):​c.56A>G​(p.His19Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H19P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VCAN NM_004385.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• Publications: 1 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 Gene-Disease associations (from GenCC):

• Wagner disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27149683).

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.56A>G	p.His19Arg	missense	Exon 2 of 15	NP_004376.2
	VCAN	NM_001164097.2		c.56A>G	p.His19Arg	missense	Exon 2 of 14	NP_001157569.1	P13611-2
	VCAN	NM_001164098.2		c.56A>G	p.His19Arg	missense	Exon 2 of 14	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.56A>G	p.His19Arg	missense	Exon 2 of 15	ENSP00000265077.3	P13611-1
	VCAN	ENST00000343200.9	TSL:1	c.56A>G	p.His19Arg	missense	Exon 2 of 14	ENSP00000340062.5	P13611-2
	VCAN	ENST00000342785.8	TSL:1	c.56A>G	p.His19Arg	missense	Exon 2 of 14	ENSP00000342768.4	P13611-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461076 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726864

African (AFR) AF: 0.0000299 AC: 1 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39584

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111502

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.17
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.029	D
Polyphen		0.81	P
Vest4		0.34
MutPred		0.49		Gain of MoRF binding (P = 0.0043)
MVP		0.78
MPC		0.098
ClinPred		0.64	D
GERP RS		4.3
Varity_R		0.067
gMVP		0.33
Mutation Taster		=82/18	polymorphism

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: rs781014698; hg19: chr5-82779393;