chr7-49775473-C-G

Position:

• chr7-49775473-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198570.5(VWC2):​c.38C>G​(p.Ser13Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000145 in 1,381,056 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VWC2 NM_198570.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.54

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWC2	NM_198570.5	c.38C>G	p.Ser13Cys	missense_variant	2/4	ENST00000340652.5	NP_940972.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWC2	ENST00000340652.5	c.38C>G	p.Ser13Cys	missense_variant	2/4	1	NM_198570.5	ENSP00000341819.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1381056 Hom.: 0 Cov.: 44 AF XY: 0.00000292 AC XY: 2 AN XY: 684272

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000613

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ExAC AF: 0.00000833 AC: 1

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

Oct 25, 2024

The c.38C>G (p.S13C) alteration is located in exon 2 (coding exon 1) of the VWC2 gene. This alteration results from a C to G substitution at nucleotide position 38, causing the serine (S) at amino acid position 13 to be replaced by a cysteine (C). 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	0.16
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0058	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.66
MutPred		0.30		Loss of loop (P = 0.0288);
MVP		0.043
MPC		2.1
ClinPred		0.66	D
GERP RS		4.7
Varity_R		0.34
gMVP		0.40

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: rs745920342; hg19: chr7-49815069;