GeneBe

SNAP25

protein-coding

synaptosome associated protein 25, the group of SNAREs

Gene summary

Synaptic vesicle membrane docking and fusion is mediated by SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) located on the vesicle membrane (v-SNAREs) and the target membrane (t-SNAREs). The assembled v-SNARE/t-SNARE complex consists of a bundle of four helices, one of which is supplied by v-SNARE and the other three by t-SNARE. For t-SNAREs on the plasma membrane, the protein syntaxin supplies one helix and the protein encoded by this gene contributes the other two. Therefore, this gene product is a presynaptic plasma membrane protein involved in the regulation of neurotransmitter release. Two alternative transcript variants encoding different protein isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:
  • SNAP

MANE transcript

NM_130811.4

Inheritance

AD

ClinVar variants

P:29U:70B:56

Top phenotype

Myasthenic syndrome, congenital 18

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr20:10,172,395-10,308,258

External References & Databases

Ensembl (ENSG00000132639)NCBI Gene (6616)OMIM (600322)HGNC:11132GenCCUniProt (P60880)AlphaFoldClinVar (SNAP25)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~135.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital myasthenic syndrome 18DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014590

Submitter: G2P

presynaptic congenital myasthenic syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020345

Submitter: Orphanet

genetic developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: ClinGen

Variants in *SNAP25* were first reported in relation to developmental and epileptic encephalopathy in 2013 (Rohena et al., PMID: 25003006). *SNAP25* encodes a synaptosomal-associated protein involved in presynaptic and postsynaptic membrane fusion. Clinical features identified in affected individuals include epilepsy, focal clonic and tonic-clonic seizures, variable developmental or intellectual disabilities, hypotonia, ataxia, and minor dysmorphic features. Thirteen unique variants (missense, nonsense, and splice site) that have been reported in 16 probands in four publications (PMIDs: 25003006, 25381298, 29100083, 33299146) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Variants are *de novo* in all probands. This gene-disease relationship is also supported by experimental evidence, including two mouse models, protein interactions between the v- and t-SNARE complexes, and a rescue model (PMIDs: 2592413, 9529252, 12859899, 17283335). In summary, there is definitive evidence supporting the relationship between *SNAP25* and autosomal dominant developmental and epileptic encephalopathy. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on March 24, 2022 (SOP Version 8).

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

congenital myasthenic syndrome 18STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014590

Submitter: Labcorp Genetics (formerly Invitae)

genetic developmental and epileptic encephalopathyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Ambry Genetics

congenital myasthenic syndrome 18LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014590

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Myasthenic syndrome, congenital 18AD

Manifestation: Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Treatment with cholinesterase inhibitor was not described as effective

Refs: 25381298Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SNAP25 variants in ClinVar

22 Conditions Cataloged
Congenital myasthenic syndrome 18Total: 178
not providedTotal: 45
Developmental and epileptic encephalopathyTotal: 25
Inborn genetic diseasesTotal: 22
SNAP25-related disorderTotal: 9
not specifiedTotal: 8
Global developmental delayTotal: 2
SNAP25-related developmental delays and epileptic encephalopathiesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_130811.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
45
clinvar
 47
missense
21
clinvar
58
clinvar
8
clinvar
2
clinvar
 89
nonsense
1
clinvar
3
clinvar
2
clinvar
1
clinvar
 7
start loss
0
frameshift
1
clinvar
1
clinvar
 2
splice donor/acceptor (+/-2bp)
3
clinvar
7
clinvar
 10
Total12870542155
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 109 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_130811.4RefSeqNP_570824.17MANE Select
ENST00000254976.7EnsemblENSP00000254976.37MANE Select
NM_001322902.2RefSeqNP_001309831.17Standard
NM_001322903.2RefSeqNP_001309832.17Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
snap25aDanio rerio

Structure: primary motor neuron

Quality: structure

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Synaptic vesicle cycle - Homo sapiens (human)
  • Insulin secretion - Homo sapiens (human)
  • Nicotine Pathway (Dopaminergic Neuron), Pharmacodynamics
  • Synaptic Vesicle Pathway
  • Insulin Signaling

Biological Process

  • neurotransmitter uptake
  • exocytosis
  • vesicle fusion
  • chemical synaptic transmission
  • locomotory behavior

Molecular Function

  • voltage-gated potassium channel activity
  • SNAP receptor activity
  • protein binding
  • syntaxin-1 binding
  • syntaxin binding

Cellular Component

  • cytoplasm
  • trans-Golgi network
  • cytosol
  • cytoskeleton
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000254976
Coding exons
7
Length
88589
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.96361310.2740.000008061391
Missense (PolyPhen)1242.0190.28559416
Synonymous1.932641.90.6210.00000251348
Loss of Function3.35013.00.007.13e-7140

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: t-SNARE involved in the molecular regulation of neurotransmitter release. May play an important role in the synaptic function of specific neuronal systems. Associates with proteins involved in vesicle docking and membrane fusion. Regulates plasma membrane recycling through its interaction with CENPF. Modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1 in pancreatic beta cells. {ECO:0000250|UniProtKB:P60881}.;
Disease
DISEASE: Myasthenic syndrome, congenital, 18 (CMS18) [MIM:616330]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS18 is an autosomal dominant presynaptic disorder clinically characterized by early-onset muscle weakness and easy fatigability associated with delayed psychomotor development and ataxia. {ECO:0000269|PubMed:25381298}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.394

Intolerance Scores

RVIS EVS
-0.01
RVIS percentile EVS
52.85

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.907

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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