7-49776013-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_198570.5(VWC2):c.578C>A(p.Pro193Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000431 in 1,392,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: VWC2 NM_198570.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.70

Genes affected

VWC2 (HGNC:30200): (von Willebrand factor C domain containing 2) This gene encodes a secreted bone morphogenic protein antagonist. The encoded protein is possibly involved in neural function and development and may have a role in cell adhesion.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWC2	NM_198570.5	c.578C>A	p.Pro193Gln	missense_variant	2/4	ENST00000340652.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWC2	ENST00000340652.5	c.578C>A	p.Pro193Gln	missense_variant	2/4	1	NM_198570.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000431 AC: 6 AN: 1392268 Hom.: 0 Cov.: 35 AF XY: 0.00000582 AC XY: 4 AN XY: 687636

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000555

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2023

The c.578C>A (p.P193Q) alteration is located in exon 2 (coding exon 1) of the VWC2 gene. This alteration results from a C to A substitution at nucleotide position 578, causing the proline (P) at amino acid position 193 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.46		Gain of relative solvent accessibility (P = 0.2751);
MVP		0.23
MPC		2.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.75
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs1788046833; hg19: chr7-49815609;