SYT2

Summary

SYT2 (synaptotagmin 2, HGNC:11510) is a protein-coding gene on chromosome 1q32.1, encoding Synaptotagmin-2 (Q8N9I0). Exhibits calcium-dependent phospholipid and inositol polyphosphate binding properties.

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.

Source: NCBI Gene 127833 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital myasthenic syndrome 7 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 338 total — 9 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 104
• MANE Select transcript: NM_177402

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11510
Approved symbol	SYT2
Name	synaptotagmin 2
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000143858
Ensembl biotype	protein_coding
OMIM	600104
Entrez	127833

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000367267, ENST00000367268, ENST00000899895, ENST00000899896, ENST00000930882, ENST00000930883

RefSeq mRNA: 2 — MANE Select: NM_177402 NM_001136504, NM_177402

CCDS: CCDS1427

Canonical transcript exons

ENST00000367268 — 9 exons

Exon	Start	End
ENSE00000962378	202604455	202604621
ENSE00000962379	202602999	202603118
ENSE00000962381	202601890	202602057
ENSE00000962385	202602378	202602545
ENSE00001305848	202710258	202710454
ENSE00001444015	202590596	202596963
ENSE00001444016	202605595	202605789
ENSE00001743748	202599218	202599351
ENSE00002228223	202600357	202600474

Expression profiles

Bgee: expression breadth ubiquitous, 165 present calls, max score 95.34.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.6731 / max 124.7091, expressed in 178 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16726	1.2207	160
16725	0.2335	77
16727	0.2190	93

Top tissues by expression

273 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	95.34	gold quality
pons	UBERON:0000988	95.01	gold quality
type B pancreatic cell	CL:0000169	94.26	gold quality
lateral globus pallidus	UBERON:0002476	93.85	gold quality
paraflocculus	UBERON:0005351	93.50	gold quality
cerebellar vermis	UBERON:0004720	93.47	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.02	gold quality
diaphragm	UBERON:0001103	91.82	gold quality
cerebellum	UBERON:0002037	91.13	gold quality
cerebellar cortex	UBERON:0002129	90.99	gold quality
cerebellar hemisphere	UBERON:0002245	90.90	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.60	gold quality
superior vestibular nucleus	UBERON:0007227	87.70	gold quality
medulla oblongata	UBERON:0001896	87.05	gold quality
substantia nigra pars compacta	UBERON:0001965	87.00	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	86.99	gold quality
substantia nigra pars reticulata	UBERON:0001966	86.71	silver quality
inferior olivary complex	UBERON:0002127	86.57	gold quality
primary visual cortex	UBERON:0002436	86.47	gold quality
occipital lobe	UBERON:0002021	86.26	gold quality
dorsal root ganglion	UBERON:0000044	86.07	gold quality
ventral tegmental area	UBERON:0002691	85.46	silver quality
dorsal plus ventral thalamus	UBERON:0001897	85.35	silver quality
inferior vagus X ganglion	UBERON:0005363	85.26	gold quality
postcentral gyrus	UBERON:0002581	84.95	gold quality
Brodmann (1909) area 23	UBERON:0013554	84.89	gold quality
left ventricle myocardium	UBERON:0006566	84.88	gold quality
parietal lobe	UBERON:0001872	84.77	gold quality
hair follicle	UBERON:0002073	84.76	gold quality
vastus lateralis	UBERON:0001379	84.16	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.51

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

197 targeting SYT2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611

Literature-anchored findings (GeneRIF, showing 13)

• role for synaptotagmin II as calcium-sensor during phagocytosis and secretion in neutrophils (PMID:12063179)
• both synaptotagmins I and II can interact with the syntaxin/synaptosomal-associated protein of 25 kDa (SNAP-25) dimer (PMID:14709554)
• WNK1 selectively binds to and phosphorylates synaptotagmin 2 (Syt2) within its calcium binding C2 domains. Endogenous WNK1 and Syt2 coimmunoprecipitate and colocalize on a subset of secretory granules in INS-1 cells. (PMID:15350218)
• A recombinant fragment from the luminal domain of the human receptor protein syt II can bind specifically to botulinum neurotoxin B and its Hc domain. (PMID:18639519)
• Mutation of overexpressed Syt2 transgene leaves intrinsic calcium sensitivity of vesicles intact while it destabilizes the readily releasable pool of vesicles and loosens the tight coupling between calcium influx and release. (PMID:19709630)
• synaptotagmin-II is not a high affinity receptor for BoNT/B and G due to a phenylalanine to leucine mutation in its luminal domain present only in humans and chimpanzees (PMID:22265973)
• Human SytII is not an effective receptor for Botulinum neurotoxin D-C. (PMID:22454523)
• Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy. (PMID:25192047)
• SYT2 mutations cause a novel complex presynaptic congenital myasthenic syndrome characterized by motor neuropathy causing lower limb wasting and foot deformities, reflex potentiation following exercise and a prolonged period of posttetanic potentiation (PMID:26519543)
• the extended synaptotagmins (E-Syts), endoplasmic reticulum (ER) proteins that function as PtdIns(4,5)P2- and Ca(2+)-regulated tethers to the Pplasma membrane. (PMID:27065097)
• Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C-terminal amino acid sequence. (PMID:32250532)
• Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome. (PMID:32776697)
• Identification of a Novel de Novo Variant in the SYT2 Gene Causing a Rare Type of Distal Hereditary Motor Neuropathy. (PMID:33105646)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	SYT2	ENSDARG00000014169
danio_rerio	syt2a	ENSDARG00000025206
mus_musculus	Syt2	ENSMUSG00000026452
rattus_norvegicus	Syt2	ENSRNOG00000004756

Paralogs (31): SYT7 (ENSG00000011347), SYT13 (ENSG00000019505), SYT1 (ENSG00000067715), RPH3A (ENSG00000089169), SYTL4 (ENSG00000102362), SYT17 (ENSG00000103528), SYT10 (ENSG00000110975), SYT5 (ENSG00000129990), SYT11 (ENSG00000132718), SYT4 (ENSG00000132872), SYT6 (ENSG00000134207), SYTL2 (ENSG00000137501), SYT16 (ENSG00000139973), SYTL1 (ENSG00000142765), SYT14 (ENSG00000143469), SYTL5 (ENSG00000147041), SYT8 (ENSG00000149043), DOC2A (ENSG00000149927), SYTL3 (ENSG00000164674), TC2N (ENSG00000165929), SYT9 (ENSG00000170743), SYT12 (ENSG00000173227), RPH3AL (ENSG00000181031), C2CD4C (ENSG00000183186), C2CD4A (ENSG00000198535), SYT15 (ENSG00000204176), C2CD4B (ENSG00000205502), SYT3 (ENSG00000213023), C2CD4D (ENSG00000225556), DOC2B (ENSG00000272636), SYT15B (ENSG00000277758)

Protein

Protein identifiers

Synaptotagmin-2 — Q8N9I0 (reviewed: Q8N9I0)

Alternative names: Synaptotagmin II

All UniProt accessions (1): Q8N9I0

UniProt curated annotations — full annotation on UniProt →

Function. Exhibits calcium-dependent phospholipid and inositol polyphosphate binding properties. May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse. Plays a role in dendrite formation by melanocytes.

Subunit / interactions. Homotetramer. Heterodimer; heterodimerizes with SYT1 in presence of calcium. Interacts with STON2. Interacts with SCAMP5. Interacts with PRRT2.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle membrane. Chromaffin granule membrane. Cytoplasm.

Tissue specificity. Expressed at the neuromuscular junction. Expressed in melanocytes.

Post-translational modifications. Phosphorylation at Thr-199 by WNK1, changes the calcium requirement for SYT2-binding to phospholipid membranes.

Disease relevance. Myasthenic syndrome, congenital, 7A, presynaptic, and distal motor neuropathy, autosomal dominant (CMS7A) [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. CMS7A 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. The disease is caused by variants affecting the gene represented in this entry. Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive (CMS7B) [MIM:619461] An autosomal recessive 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. CMS7B is characterized by defects at the pre-synaptic neuromuscular junction and severe generalized muscle weakness apparent from birth. Decreased fetal movements may be apparent in utero. Affected infants have generalized hypotonia, head lag, and facial muscle weakness with ptosis. Some patients may have respiratory involvement. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 3 Ca(2+) ions per subunit. The ions are bound to the C2 domains.

Domain organisation. The first C2 domain mediates Ca(2+)-dependent phospholipid binding. The second C2 domain mediates interaction with Stonin 2. The second C2 domain mediates phospholipid and inositol polyphosphate binding in a calcium-independent manner.

Similarity. Belongs to the synaptotagmin family.

RefSeq proteins (2): NP_001129976, NP_796376* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR001565	Synaptotagmin	Domain
IPR035892	C2_domain_sf	Homologous_superfamily

Pfam: PF00168

UniProt features (42 total): binding site 18, sequence variant 6, modified residue 5, region of interest 3, topological domain 2, domain 2, chain 1, transmembrane region 1, glycosylation site 1, sequence conflict 1, helix 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6G5G	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N9I0-F1	81.64	0.57

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (18): 169; 170; 170; 176; 228; 228; 229; 230; 230; 230; 233; 234 …

Post-translational modifications (5): 122, 125, 199, 227, 383

Glycosylation sites (1): 29

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-5250958	Toxicity of botulinum toxin type B (botB)
R-HSA-6794361	Neurexins and neuroligins
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-112316	Neuronal System
R-HSA-1643685	Disease
R-HSA-168799	Neurotoxicity of clostridium toxins
R-HSA-199991	Membrane Trafficking
R-HSA-5339562	Uptake and actions of bacterial toxins
R-HSA-5653656	Vesicle-mediated transport
R-HSA-5663205	Infectious disease
R-HSA-6794362	Protein-protein interactions at synapses
R-HSA-9824439	Bacterial Infection Pathways

MSigDB gene sets: 426 (showing top): AP1_01, GOBP_REGULATION_OF_VESICLE_FUSION, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_NEURON_PROJECTION_EXTENSION, GOCC_SECRETORY_GRANULE, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_VESICLE_ORGANIZATION, AREB6_03, GOBP_MEMBRANE_FUSION, GOBP_GROWTH, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING

GO Biological Process (6): vesicle-mediated transport (GO:0016192), regulation of calcium ion-dependent exocytosis (GO:0017158), cell differentiation (GO:0030154), calcium-dependent activation of synaptic vesicle fusion (GO:0099502), positive regulation of dendrite extension (GO:1903861), regulation of synaptic vesicle exocytosis (GO:2000300)

GO Molecular Function (6): SNARE binding (GO:0000149), calcium-dependent phospholipid binding (GO:0005544), inositol 1,3,4,5 tetrakisphosphate binding (GO:0043533), metal ion binding (GO:0046872), calcium ion sensor activity (GO:0061891), protein binding (GO:0005515)

GO Cellular Component (11): plasma membrane (GO:0005886), axon (GO:0030424), clathrin-coated endocytic vesicle membrane (GO:0030669), synaptic vesicle membrane (GO:0030672), dense core granule (GO:0031045), chromaffin granule membrane (GO:0042584), exocytic vesicle (GO:0070382), cytoplasm (GO:0005737), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Neurotoxicity of clostridium toxins	1
Protein-protein interactions at synapses	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
Uptake and actions of bacterial toxins	1
Vesicle-mediated transport	1
Bacterial Infection Pathways	1
Disease	1
Neuronal System	1
Infectious disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of regulated secretory pathway	2
synaptic vesicle exocytosis	2
cellular anatomical structure	2
transport	1
cellular process	1
calcium-ion regulated exocytosis	1
cellular developmental process	1
positive regulation of synaptic vesicle fusion to presynaptic active zone membrane	1
positive regulation of cell growth	1
positive regulation of developmental growth	1
dendrite extension	1
regulation of dendrite extension	1
regulation of neurotransmitter secretion	1
protein binding	1
phospholipid binding	1
anion binding	1
alcohol binding	1
cation binding	1
calcium ion binding	1
metal ion sensor activity	1
binding	1
membrane	1
cell periphery	1
neuron projection	1
clathrin-coated vesicle membrane	1
endocytic vesicle membrane	1
clathrin-coated endocytic vesicle	1
synaptic vesicle	1
exocytic vesicle membrane	1
secretory granule	1
secretory granule membrane	1
chromaffin granule	1
transport vesicle	1
secretory vesicle	1
intracellular anatomical structure	1
cytoplasm	1
intracellular vesicle	1
cell junction	1

Protein interactions and networks

STRING

1746 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SYT2	STON2	Q8WXE9	860
SYT2	OTOF	Q9HC10	840
SYT2	STX1A	Q16623	829
SYT2	VAMP2	P19065	773
SYT2	SYN1	P17600	741
SYT2	SV2A	Q7L0J3	735
SYT2	CPLX1	O14810	731
SYT2	SNAP25	P13795	714
SYT2	CTBP2	P56545	708
SYT2	WNK1	P54963	700
SYT2	VAMP1	P23763	670
SYT2	SYP	P08247	663
SYT2	CACNA1D	Q01668	658
SYT2	UNC13B	O14795	637
SYT2	ITSN1	Q15811	631

IntAct

108 interactions, top by confidence:

A	B	Type	Score
SYT1	SYT2	psi-mi:“MI:0915”(physical association)	0.710
HTT	SYT2	psi-mi:“MI:0915”(physical association)	0.670
ACADL	SYT2	psi-mi:“MI:0915”(physical association)	0.590
SYT2	CCDC167	psi-mi:“MI:0915”(physical association)	0.560
MALL	SYT2	psi-mi:“MI:0915”(physical association)	0.560
MIP	SYT2	psi-mi:“MI:0915”(physical association)	0.560
SLC35A1	SYT2	psi-mi:“MI:0915”(physical association)	0.560
SYT2	TMEM229B	psi-mi:“MI:0915”(physical association)	0.560
TF	SYT2	psi-mi:“MI:0915”(physical association)	0.560
ORMDL3	SYT2	psi-mi:“MI:0915”(physical association)	0.560
ITGAM	SYT2	psi-mi:“MI:0915”(physical association)	0.560
SYT2	CMTM3	psi-mi:“MI:0915”(physical association)	0.560
TSPO2	SYT2	psi-mi:“MI:0915”(physical association)	0.560
THSD7B	SYT2	psi-mi:“MI:0915”(physical association)	0.560
SYT2	AQP10	psi-mi:“MI:0915”(physical association)	0.560
SYT2	NAPB	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	SYT2	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	SYT2	psi-mi:“MI:0915”(physical association)	0.560
FA2H	SYT2	psi-mi:“MI:0915”(physical association)	0.560
PLPP4	SYT2	psi-mi:“MI:0915”(physical association)	0.560
SYT2	SLC35A4	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (137): SYT2 (Affinity Capture-MS), SYT2 (Affinity Capture-MS), SYT2 (Affinity Capture-MS), SYT2 (Affinity Capture-RNA), SYT2 (Two-hybrid), SYT2 (Two-hybrid), SYT2 (Two-hybrid), SYT2 (Two-hybrid), SYT2 (Two-hybrid), SYT2 (Two-hybrid), SYT2 (Two-hybrid), SYT2 (Two-hybrid), SYT2 (Two-hybrid), SYT2 (Two-hybrid), MALL (Two-hybrid)

ESM2 similar proteins: A0A075F932, A8KBH6, F1LM93, K8FE10, O08625, O08835, P04409, P05126, P05130, P05696, P05771, P05772, P10102, P13217, P17252, P20444, P21521, P21579, P21707, P24505, P24506, P24507, P25455, P29101, P34693, P40749, P41823, P46096, P46097, P47191, P47861, P48018, P50232, P68403, P68404, P70169, P70610, P90980, Q14184, Q5FWL4

Diamond homologs: A0A075F932, A0FGR8, A4IJ05, K8FE10, O00445, O00750, O08625, O08835, O35681, O43581, P04409, P05128, P05129, P05130, P05696, P10102, P10829, P13677, P17252, P20444, P21521, P21579, P21707, P24505, P24506, P24507, P29101, P34693, P40748, P40749, P41823, P41885, P46096, P46097, P47191, P47708, P47709, P47861, P48018, P50232

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
WNK1	“up-regulates activity”	SYT2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

338 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	8
Uncertain significance	166
Likely benign	111
Benign	28

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1192311	NM_177402.5(SYT2):c.1112T>A (p.Ile371Lys)	Pathogenic
1192312	NM_177402.5(SYT2):c.1082_1096del (p.Asp361_Leu365del)	Pathogenic
1192313	NM_177402.5(SYT2):c.1094T>C (p.Leu365Pro)	Pathogenic
1192314	NM_177402.5(SYT2):c.805G>T (p.Glu269Ter)	Pathogenic
1192315	NM_177402.5(SYT2):c.1191del (p.Arg397fs)	Pathogenic
1192316	NM_177402.5(SYT2):c.465+1G>A	Pathogenic
1192317	NM_177402.5(SYT2):c.725dup (p.Val243fs)	Pathogenic
156368	NM_177402.5(SYT2):c.920A>C (p.Asp307Ala)	Pathogenic
2130774	NM_177402.5(SYT2):c.686_687del (p.Asp228_Phe229insTer)	Pathogenic
1516278	NM_177402.5(SYT2):c.919+1G>A	Likely pathogenic
1698082	NM_177402.5(SYT2):c.917C>T (p.Ser306Leu)	Likely pathogenic
2505353	NM_177402.5(SYT2):c.207del (p.Val70fs)	Likely pathogenic
2631391	NM_177402.5(SYT2):c.179-1G>A	Likely pathogenic
3064703	NM_177402.5(SYT2):c.548_549delinsGGA (p.Leu183fs)	Likely pathogenic
373966	NM_177402.5(SYT2):c.1084_1089del (p.Tyr362_Asp363del)	Likely pathogenic
3767275	NM_177402.5(SYT2):c.54del (p.Thr19fs)	Likely pathogenic
4278115	NM_177402.5(SYT2):c.1017G>C (p.Glu339Asp)	Likely pathogenic

SpliceAI

2513 predictions. Top by Δscore:

Variant	Effect	Δscore
1:202596689:A:C	donor_gain	1.0000
1:202596754:TGTC:T	donor_gain	1.0000
1:202596788:T:TA	donor_gain	1.0000
1:202596960:CTTT:C	acceptor_gain	1.0000
1:202596963:TCT:T	acceptor_loss	1.0000
1:202596964:C:A	acceptor_loss	1.0000
1:202596964:C:CC	acceptor_gain	1.0000
1:202599213:AGCAC:A	donor_loss	1.0000
1:202599214:GCACC:G	donor_loss	1.0000
1:202599216:ACCTG:A	donor_loss	1.0000
1:202599217:CCTG:C	donor_loss	1.0000
1:202599347:CGGGT:C	acceptor_gain	1.0000
1:202599351:TC:T	acceptor_loss	1.0000
1:202599352:C:CC	acceptor_gain	1.0000
1:202599352:CTGCG:C	acceptor_loss	1.0000
1:202600352:CGTA:C	donor_loss	1.0000
1:202600353:GTACC:G	donor_loss	1.0000
1:202600354:TA:T	donor_loss	1.0000
1:202600355:A:AT	donor_loss	1.0000
1:202600471:CCGG:C	acceptor_gain	1.0000
1:202600472:CGG:C	acceptor_gain	1.0000
1:202600472:CGGC:C	acceptor_gain	1.0000
1:202600474:GCTG:G	acceptor_loss	1.0000
1:202600475:C:CC	acceptor_gain	1.0000
1:202600480:C:CT	acceptor_gain	1.0000
1:202600480:C:T	acceptor_gain	1.0000
1:202600481:A:T	acceptor_gain	1.0000
1:202601888:ACCT:A	donor_gain	1.0000
1:202601889:CCTC:C	donor_gain	1.0000
1:202601891:T:TA	donor_gain	1.0000

AlphaMissense

2791 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:202596803:A:G	L405P	1.000
1:202596803:A:T	L405H	1.000
1:202596811:C:A	W402C	1.000
1:202596811:C:G	W402C	1.000
1:202596812:C:A	W402L	1.000
1:202596812:C:G	W402S	1.000
1:202596813:A:G	W402R	1.000
1:202596813:A:T	W402R	1.000
1:202596815:T:G	Q401P	1.000
1:202596818:G:T	A400D	1.000
1:202596824:G:C	P398R	1.000
1:202596824:G:T	P398H	1.000
1:202596826:C:A	R397S	1.000
1:202596826:C:G	R397S	1.000
1:202596827:C:A	R397M	1.000
1:202596827:C:G	R397T	1.000
1:202596831:G:A	R396W	1.000
1:202596842:A:G	L392P	1.000
1:202596845:A:C	M391R	1.000
1:202596845:A:T	M391K	1.000
1:202596853:C:A	W388C	1.000
1:202596853:C:G	W388C	1.000
1:202596854:C:G	W388S	1.000
1:202596855:A:G	W388R	1.000
1:202596855:A:T	W388R	1.000
1:202596888:C:G	G377R	1.000
1:202596902:C:A	G372V	1.000
1:202596902:C:T	G372D	1.000
1:202596903:C:A	G372C	1.000
1:202596903:C:G	G372R	1.000

dbSNP variants (sampled 300 via entrez): RS1000002090 (1:202679928 G>A), RS1000021326 (1:202641639 C>T), RS1000029093 (1:202702194 C>A,T), RS1000092087 (1:202596102 G>C), RS1000104373 (1:202689566 C>A), RS1000124751 (1:202595630 G>C), RS1000166512 (1:202711068 A>G), RS1000252747 (1:202662566 G>A), RS1000261705 (1:202623128 G>A,T), RS1000339872 (1:202673877 C>T), RS1000442589 (1:202629035 C>A), RS1000474018 (1:202657707 G>A), RS1000474328 (1:202694644 C>A,T), RS1000483541 (1:202665950 G>A), RS1000568028 (1:202618813 C>CCCTCA)

Disease associations

OMIM: gene MIM:600104 | disease phenotypes: MIM:616040, MIM:619461, MIM:117000, MIM:601462

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital myasthenic syndrome 7	Strong	Autosomal dominant
myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive	Strong	Autosomal recessive
presynaptic congenital myasthenic syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital myasthenic syndrome 7	Moderate	AD

Mondo (6): congenital myasthenic syndrome 7 (MONDO:0014468), myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive (MONDO:0030341), congenital myopathy (MONDO:0019952), congenital myasthenic syndrome (MONDO:0018940), axonal neuropathy (MONDO:0004183), (MONDO:0020345)

Orphanet (2): Congenital myasthenic syndrome (Orphanet:590), Congenital myopathy (Orphanet:97245)

HPO phenotypes

104 total (30 of 104 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000276	Long face
HP:0000308	Microretrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000467	Neck muscle weakness
HP:0000508	Ptosis
HP:0000514	Slow saccadic eye movements
HP:0000565	Esotropia
HP:0000602	Ophthalmoplegia
HP:0000639	Nystagmus
HP:0000651	Diplopia
HP:0000768	Pectus carinatum
HP:0000961	Cyanosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001283	Bulbar palsy
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001308	Tongue fasciculations
HP:0001320	Cerebellar vermis hypoplasia
HP:0001374	Congenital hip dislocation

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002112_2	Celiac disease	3.000000e-07
GCST002949_1	Epilepsy and lamotrigine-induced maculopapular eruptions	4.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:1001253	maculopapular eruption

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D020294	Myasthenic Syndromes, Congenital	C10.668.758.800; C16.320.590

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Valproic Acid	affects expression, increases expression	2
Aflatoxin B1	affects methylation, decreases expression, increases methylation	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
terbufos	increases methylation	1
butyraldehyde	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Allergens	increases expression	1
Copper	affects cotreatment, decreases expression	1
Fonofos	increases methylation	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment, decreases expression	1
Parathion	increases methylation	1
Smoke	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Toluene	affects cotreatment, decreases expression	1
Xylenes	decreases expression, affects cotreatment	1
1-Methyl-4-phenylpyridinium	increases expression	1
Okadaic Acid	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TR38	HAP1 SYT2 (-) 1	Cancer cell line	Male
CVCL_TR39	HAP1 SYT2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

26 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01203592	PHASE1	COMPLETED	Efficacy of Albuterol in the Treatment of Congenital Myasthenic Syndromes
NCT06436742	PHASE1	RECRUITING	A Phase 1b Study to Investigate Safety and Tolerability of ARGX-119 in Adult Participants With DOK7-Congenital Myasthenic Syndromes (CMS)
NCT07226726	PHASE1	RECRUITING	Patients With Congenital Myasthenic Syndrome Will be Treated With Mesenchymal Stem Cell Exosome Solution
NCT02020187	Not specified	COMPLETED	Aerobic Training in Patients With Congenital Myopathies
NCT03018184	Not specified	COMPLETED	Contractile Cross Sectional Areas and Muscle Strength in Patients With Congenital Myopathies
NCT04733976	Not specified	COMPLETED	Bullying in Youth With Muscular Dystrophy and Congenital Myopathies
NCT05099107	Not specified	COMPLETED	Changes of Motor Function Tests in Congenital Myopathy Subjects Treated With Oral Salbutamol as Compared to no Treatment
NCT05199246	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Lower-limb Powered Dermoskeleton in Patients With Neuromuscular Disorders
NCT05200702	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Knee-hip Powered Soft Exoskeleton in Patients With Neuromuscular Disorders
NCT05692349	Not specified	UNKNOWN	Magnetic Resonance Imaging and Ultrasonography in Evaluation of Muscle Diseases
NCT06791369	Not specified	NOT_YET_RECRUITING	The Prevalence of RYR1-related Disease
NCT06833489	Not specified	RECRUITING	Transcriptomic Analysis to Put an End to Misdiagnosis in Patients With Rare Muscle Diseases
NCT07138963	Not specified	RECRUITING	Phenotype - Genotype Correlation in a Sample of Egyptian Patients With Congenital Myopathies and Congenital Muscular Dystrophies
NCT07415837	Not specified	RECRUITING	Evaluation of the Role of miR-1 in the Pathogenesis and as a Biomarker in Muscular Dystrophies and Congenital Myopathies
NCT07502989	Not specified	RECRUITING	Muscle Health Measurements Using Electrical Impedance Myography
NCT07580365	Not specified	NOT_YET_RECRUITING	VirtualPark_Pediatric
NCT00872950	Not specified	APPROVED_FOR_MARKETING	3,4-Diaminopyridine Use in Lambert-Eaton Myasthenic Syndrome(LEMS) and Congenital Myasthenic Syndromes (CMS)
NCT01403402	Not specified	RECRUITING	Congenital Muscle Disease Study of Patient and Family Reported Medical Information
NCT01474980	Not specified	COMPLETED	Pregnancy Outcomes in Congenital Myasthenie Syndrome
NCT02012933	Not specified	NO_LONGER_AVAILABLE	3,4-Diaminopyridine for Lambert-Eaton Myasthenic Syndrome (LEMS) and Congenital Myasthenia (CM)
NCT02189720	Not specified	APPROVED_FOR_MARKETING	Expanded Access Study Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS),Congenital Myasthenic Syndrome
NCT03062631	Not specified	NO_LONGER_AVAILABLE	Treatment Use of 3,4 Diaminopyridine in Congenital Myasthenia
NCT05408702	Not specified	COMPLETED	Exercise in Autoimmune Myasthenia Gravis and Myasthenic Syndromes
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06078553	Not specified	RECRUITING	A Natural History Study in Participants With Congenital Myasthenic Syndromes (CMS) Due to Mutations in DOK7, MUSK, AGRN, or LRP4
NCT01847937	Not specified	COMPLETED	Magnetic Resonance Diagnostics of Diabetic Peripheral Neuropathy