17-8161667-A-G
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
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
NM_014232.3 missense
Scores
9
8
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a mutagenesis_site Significant loss of phosphorylation; when associated with A-28, A-61 and A-80. (size 0) in uniprot entity VAMP2_HUMAN
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
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
.;H;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;D;.;D;.
REVEL
Uncertain
Sift
Uncertain
.;D;.;D;.
Sift4G
Uncertain
.;.;D;D;.
Polyphen
0.99
.;D;.;.;.
Vest4
0.73, 0.74, 0.73, 0.73
MutPred
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
MPC
3.0
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at