SYT2
protein-codingsynaptotagmin 2, the group of Synaptotagmins
Gene summary
This gene encodes a synaptic vesicle membrane protein. The encoded protein is thought to function as a calcium sensor in vesicular trafficking and exocytosis. Mutations in this gene are associated with myasthenic syndrome, presynaptic, congenital, with or without motor neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~119.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014468
Submitter: ClinGen
SYT2 was first reported in relation to autosomal dominant presynaptic congenital myasthenic syndrome 7A and distal motor neuropathy (CMS7A) in 2014 (Hermann et al., PMID: 25192047). Patients present with early onset foot deformities and distal muscle weakness. Electrophysiologic studies show abnormal synaptic transmission at the neuromuscular junction (NMJ) and low amplitude compound muscle action potentials. SYT2 has also been associated with autosomal recessive presynaptic congenital myasthenic syndrome 7B (CMS7B). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into autosomal dominant CMS7A (OMIM: 616040) and autosomal recessive CMS7A (OMIM: 619461). Six variants (missense and in-frame deletion) reported in six probands in five publications were included in this curation, reaching a total of five points for genetic evidence (PMID: 30533528, PMID: 25192047, PMID: 33105646, PMID: 33320396, PMID: 34037996). SYT2 encodes for Synaptotagmin 2, a calcium sensor protein involved in synaptic vesicle exocytosis at the NMJ. Variants cluster in the C2B calcium binding domain and are upgraded if located in a hotspot region. Variants were also upgraded for presenting with very consistent phenotypes. Evidence supporting this gene-disease relationship includes experimental data from two model systems: a transgenic drosophila model and a knockout mouse model. DSYT1 in drosophila is a single homolog for SYT1, SYT2, and SYT9 in humans. DSYT1 null drosophila exhibit abnormal synaptic transmission at the NMJ (PMID: 25192047). Transgenes of WT and the mutation homologous to the human Asp307Ala variant were expressed in DSYT1 null drosophila. Staining revealed co-localization of WT and mutant Synaptotagmins. Expression of WT Synaptotagmin showed phenotypic rescue in DSYT1 null drosophila, while expression of mutant Synaptotagmin failed to rescue the phenotype. Expression of mutant synaptotagmin in the presence of endogenous DSYT1 provided evidence of a dominant negative effect. This model was also used to study the Ile371Lys variant and produced similar findings for co-localization, failure of phenotypic rescue with expression of mutant synaptotagmin, and a dominant negative effect with expression of mutant Synaptotagmin in the presence of endogenous DSYT1 (PMID: 30533528). A SYT2 knockout mouse model was generated in 2006 (PMID: 17192432). The knockout was lethal and mice developed abnormal synaptic transmission at the neuromuscular junction. No rescue experiments were attempted. The drosophila model received 1.5 points and the mouse model received 1 point as experimental evidence. Both were downgraded for not representing an autosomal dominant mode of inheritance as a knockout model. In summary, there is moderate evidence to support this autosomal dominant gene-disease relationship. No contradictory evidence has emerged.
Inheritance Pattern: AR
Disease ID:MONDO:0030341
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014468
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0030341
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014468
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014468
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0014468
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Neurologic
Intervention: Musculoskeletal; Neurologic
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SYT2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_177402.5. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 64 | 4 | 70 | ||
| missense | 3 | 3 | 144 | 3 | 153 | |
| nonsense | 1 | 2 | 3 | |||
| start loss | 1 | 1 | 2 | |||
| frameshift | 3 | 3 | 2 | 8 | ||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 2 | 6 | ||
| Total | 8 | 9 | 153 | 68 | 4 | 242 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_796376.2 | 8 | MANE Select | |
| Ensembl | ENSP00000356237.4 | 8 | MANE Select | |
| RefSeq | NP_001129976.1 | 8 | Standard | |
| Ensembl | ENSP00000356236.1 | 8 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| syt2b | Danio rerio | Structure: motor neuron Quality: physical object quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Disease
- Vesicle-mediated transport
- Membrane Trafficking
- Uptake and actions of bacterial toxins
- Neurotoxicity of clostridium toxins
Biological Process
- regulation of dopamine secretion
- synaptic vesicle exocytosis
- vesicle-mediated transport
- calcium ion regulated exocytosis
- regulation of calcium ion-dependent exocytosis
Molecular Function
- SNARE binding
- phosphatidylserine binding
- calcium ion binding
- protein binding
- calcium-dependent phospholipid binding
Cellular Component
- plasma membrane
- integral component of membrane
- cell junction
- axon
- clathrin-coated vesicle membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000367267
- Coding exons
- 8
- Length
- 119822
- Individuals with no LoFs
- 125743
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 125748
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.98 | 159 | 246 | 0.645 | 0.0000135 | 2788 |
| Missense (PolyPhen) | 42 | 81.221 | 0.51711 | 950 | ||
| Synonymous | 0.887 | 91 | 102 | 0.888 | 0.00000643 | 788 |
| Loss of Function | 3.54 | 1 | 16.6 | 0.0604 | 6.99e-7 | 223 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Exhibits calcium-dependent phospholipid and inositol polyphosphate binding properties (By similarity). May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse (By similarity). Plays a role in dendrite formation by melanocytes (PubMed:23999003). {ECO:0000250|UniProtKB:P46097, ECO:0000269|PubMed:23999003}.;
- Disease
- DISEASE: Myasthenic syndrome, congenital, 7, presynaptic (CMS7) [MIM:616040]: 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. CMS7 is an autosomal dominant, presynaptic disorder resembling Lambert-Eaton myasthenic syndrome. Affected individuals have a variable degree of proximal and distal limb weakness, muscle fatigue that improves with rest, mild gait difficulties, and reduced or absent deep tendon reflexes. {ECO:0000269|PubMed:25192047}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.246
Intolerance Scores
- LoFtool
- 0.225
- RVIS EVS
- -0.63
- RVIS percentile EVS
- 17.03
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.792
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |