17-8162296-G-C

Position:

• chr17-8162296-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014232.3(VAMP2):​c.76C>G​(p.Leu26Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,441,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VAMP2 NM_014232.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 6.97

Genes affected

VAMP2 (HGNC:12643): (vesicle associated membrane protein 2) The protein encoded by this gene is a member of the vesicle-associated membrane protein (VAMP)/synaptobrevin family. Synaptobrevins/VAMPs, syntaxins, and the 25-kD synaptosomal-associated protein SNAP25 are the main components of a protein complex involved in the docking and/or fusion of synaptic vesicles with the presynaptic membrane. This gene is thought to participate in neurotransmitter release at a step between docking and fusion. The protein forms a stable complex with syntaxin, synaptosomal-associated protein, 25 kD, and synaptotagmin. It also forms a distinct complex with synaptophysin. It is a likely candidate gene for familial infantile myasthenia (FIMG) because of its map location and because it encodes a synaptic vesicle protein of the type that has been implicated in the pathogenesis of FIMG. [provided by RefSeq, Jul 2008]

ENSG00000263620 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08091304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VAMP2	NM_014232.3	c.76C>G	p.Leu26Val	missense_variant	2/5	ENST00000316509.11	NP_055047.2
VAMP2	NM_001330125.1	c.82C>G	p.Leu28Val	missense_variant	2/5		NP_001317054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VAMP2	ENST00000316509.11	c.76C>G	p.Leu26Val	missense_variant	2/5	1	NM_014232.3	ENSP00000314214.6
ENSG00000263620	ENST00000498285.1	c.76C>G	p.Leu26Val	missense_variant	2/5	4		ENSP00000464383.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441720 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 717494

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: 9.05e-7

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

VAMP2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2024

The VAMP2 c.82C>G variant is predicted to result in the amino acid substitution p.Leu28Val. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Benign	0.54
DEOGEN2	Benign	0.28	.;T;.;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.081	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;L;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.45	.;N;N;.
REVEL	Benign	0.11
Sift	Benign	0.74	.;T;T;.
Sift4G	Benign	0.33	.;.;T;.
Polyphen		0.0	.;B;.;.
Vest4		0.089, 0.095
MutPred		0.15		Gain of glycosylation at T27 (P = 0.1207);Gain of glycosylation at T27 (P = 0.1207);.;Gain of glycosylation at T27 (P = 0.1207);
MVP		0.040
MPC		0.10
ClinPred		0.25	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.16
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-8065614;