7-49775818-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_198570.5(VWC2):c.383A>G(p.Gln128Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000339 in 1,542,826 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: VWC2 NM_198570.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032797337).
• BS2: High AC in GnomAd at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWC2	NM_198570.5	c.383A>G	p.Gln128Arg	missense_variant	2/4	ENST00000340652.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWC2	ENST00000340652.5	c.383A>G	p.Gln128Arg	missense_variant	2/4	1	NM_198570.5	P1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000277 AC: 38 AN: 137014 Hom.: 1 AF XY: 0.000309 AC XY: 23 AN XY: 74532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000410

Gnomad ASJ exome AF: 0.000625

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000273

Gnomad FIN exome AF: 0.000571

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000344 AC: 479 AN: 1390522 Hom.: 1 Cov.: 36 AF XY: 0.000382 AC XY: 262 AN XY: 685386

Gnomad4 AFR exome AF: 0.0000642

Gnomad4 AMR exome AF: 0.0000561

Gnomad4 ASJ exome AF: 0.000680

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000305

Gnomad4 FIN exome AF: 0.000734

Gnomad4 NFE exome AF: 0.000344

Gnomad4 OTH exome AF: 0.000520

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74478

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000537 Hom.: 0

Bravo AF: 0.000302

ExAC AF: 0.0000692 AC: 7

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

May 11, 2022

The c.383A>G (p.Q128R) alteration is located in exon 2 (coding exon 1) of the VWC2 gene. This alteration results from a A to G substitution at nucleotide position 383, causing the glutamine (Q) at amino acid position 128 to be replaced by an arginine (R). 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	Benign	0.070
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0063	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.94	N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.057
Sift	Benign	0.092	T
Sift4G	Benign	0.22	T
Polyphen		0.031	B
Vest4		0.21
MutPred		0.22		Gain of methylation at Q128 (P = 0.0336);
MVP		0.082
MPC		1.1
ClinPred		0.040	T
GERP RS		4.0
Varity_R		0.16
gMVP		0.41

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: rs543106702; hg19: chr7-49815414;