2-214575813-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001080500.4(VWC2L):c.662C>G(p.Thr221Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VWC2L NM_001080500.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

Genes affected

VWC2L (HGNC:37203): (von Willebrand factor C domain containing 2 like) Predicted to be involved in negative regulation of BMP signaling pathway. Predicted to act upstream of or within positive regulation of neuron differentiation. Predicted to be located in extracellular region and synapse. Predicted to be part of AMPA glutamate receptor complex. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044854254).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWC2L	NM_001080500.4	c.662C>G	p.Thr221Ser	missense_variant	4/4	ENST00000312504.10
VWC2L	NM_001345929.2	c.*112C>G		3_prime_UTR_variant	3/3
VWC2L	NR_159945.1	n.1625C>G		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWC2L	ENST00000312504.10	c.662C>G	p.Thr221Ser	missense_variant	4/4	1	NM_001080500.4	P1
VWC2L	ENST00000427124.1	c.*112C>G		3_prime_UTR_variant	3/3	1
	ENST00000412896.5	n.177+107269G>C		intron_variant, non_coding_transcript_variant		4
	ENST00000437883.1	n.133-102044G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460070 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726250

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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 07, 2023

The c.662C>G (p.T221S) alteration is located in exon 4 (coding exon 3) of the VWC2L gene. This alteration results from a C to G substitution at nucleotide position 662, causing the threonine (T) at amino acid position 221 to be replaced by a serine (S). 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	0.067
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.075
Sift	Benign	0.46	T
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.21		Loss of solvent accessibility (P = 0.0576);
MVP		0.043
MPC		0.51
ClinPred		0.19	T
GERP RS		2.5
Varity_R		0.034
gMVP		0.21

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: rs377151180; hg19: chr2-215440537;