17-8161667-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_014232.3(VAMP2):c.223T>C(p.Ser75Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VAMP2 NM_014232.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_014232.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• PP5: Variant 17-8161667-A-G is Pathogenic according to our data. Variant chr17-8161667-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 810675.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-8161667-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAMP2	NM_014232.3	c.223T>C	p.Ser75Pro	missense_variant	3/5	ENST00000316509.11
VAMP2	NM_001330125.1	c.229T>C	p.Ser77Pro	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAMP2	ENST00000316509.11	c.223T>C	p.Ser75Pro	missense_variant	3/5	1	NM_014232.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 31, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
Polyphen		0.99	.;D;.;.;.
Vest4		0.73, 0.74, 0.73, 0.73
MutPred		0.52		Loss of phosphorylation at S75 (P = 0.0634);Loss of phosphorylation at S75 (P = 0.0634);.;.;Loss of phosphorylation at S75 (P = 0.0634);
MVP		0.62
MPC		3.0
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.99

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: rs1598265387; hg19: chr17-8064985;