chr7-49775640-G-A

Position:

• chr7-49775640-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_198570.5(VWC2):​c.205G>A​(p.Glu69Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000799 in 1,377,200 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E69Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000080 (0 hom.)
• Consequence: VWC2 NM_198570.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12191543).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWC2	NM_198570.5	c.205G>A	p.Glu69Lys	missense_variant	2/4	ENST00000340652.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWC2	ENST00000340652.5	c.205G>A	p.Glu69Lys	missense_variant	2/4	1	NM_198570.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000799 AC: 11 AN: 1377200 Hom.: 0 Cov.: 44 AF XY: 0.00000736 AC XY: 5 AN XY: 679156

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: 0.00000932

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000372 Hom.: 0

Bravo AF: 0.0000151

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

Apr 30, 2024

The c.205G>A (p.E69K) alteration is located in exon 2 (coding exon 1) of the VWC2 gene. This alteration results from a G to A substitution at nucleotide position 205, causing the glutamic acid (E) at amino acid position 69 to be replaced by a lysine (K). 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	0.15
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0062	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	0.70	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.13
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.52	P
Vest4		0.30
MutPred		0.12		Gain of MoRF binding (P = 0.0153);
MVP		0.068
MPC		1.2
ClinPred		0.81	D
GERP RS		3.0
Varity_R		0.13
gMVP		0.51

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: rs1242221544; hg19: chr7-49815236;