EFHC1

Summary

EFHC1 (EF-hand domain containing 1, HGNC:16406) is a protein-coding gene on chromosome 6p12.2, encoding EF-hand domain-containing protein 1 (Q5JVL4). Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.

This gene encodes an EF-hand-containing calcium binding protein. The encoded protein likely plays a role in calcium homeostasis. Mutations in this gene have been associated with susceptibility to juvenile myoclonic epilepsy and juvenile absence epilepsy. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 114327 — RefSeq curated summary.

At a glance

• Gene–disease (curated): juvenile myoclonic epilepsy (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 475 total — 2 pathogenic
• Phenotypes (HPO): 23
• MANE Select transcript: NM_018100

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16406
Approved symbol	EFHC1
Name	EF-hand domain containing 1
Location	6p12.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10466, RIB72, POC9
Ensembl gene	ENSG00000096093
Ensembl biotype	protein_coding
OMIM	608815
Entrez	114327

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 21 protein_coding, 9 protein_coding_CDS_not_defined, 8 nonsense_mediated_decay, 5 retained_intron

ENST00000371068, ENST00000480623, ENST00000481466, ENST00000491749, ENST00000538167, ENST00000635760, ENST00000635812, ENST00000635843, ENST00000635866, ENST00000635911, ENST00000635963, ENST00000635984, ENST00000635996, ENST00000636107, ENST00000636169, ENST00000636253, ENST00000636311, ENST00000636343, ENST00000636379, ENST00000636398, ENST00000636489, ENST00000636566, ENST00000636616, ENST00000636702, ENST00000636713, ENST00000636954, ENST00000637089, ENST00000637121, ENST00000637200, ENST00000637263, ENST00000637315, ENST00000637340, ENST00000637353, ENST00000637602, ENST00000637849, ENST00000637874, ENST00000637892, ENST00000638075, ENST00000638140, ENST00000914230, ENST00000914231, ENST00000953671, ENST00000953672

RefSeq mRNA: 2 — MANE Select: NM_018100 NM_001172420, NM_018100

CCDS: CCDS4942, CCDS55021

Canonical transcript exons

ENST00000371068 — 11 exons

Exon	Start	End
ENSE00000756172	52454095	52454287
ENSE00001225881	52452688	52452837
ENSE00002159915	52438304	52438591
ENSE00003499483	52423946	52424167
ENSE00003527710	52479037	52479250
ENSE00003533284	52490140	52490350
ENSE00003564585	52464895	52465115
ENSE00003591166	52492270	52497198
ENSE00003635077	52479640	52479787
ENSE00003677433	52469333	52469473
ENSE00003795985	52420342	52420473

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 99.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.1860 / max 211.0777, expressed in 1719 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
68227	15.4614	1656
68234	7.3850	1451
68233	5.5925	1549
68236	0.4309	249
68235	0.3024	97
68226	0.1888	73
68237	0.1813	68
68228	0.0745	29
204023	0.0306	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	99.52	gold quality
epithelium of bronchus	UBERON:0002031	99.35	gold quality
bronchus	UBERON:0002185	99.10	gold quality
right uterine tube	UBERON:0001302	98.79	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.46	gold quality
sperm	CL:0000019	97.70	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.04	gold quality
caput epididymis	UBERON:0004358	96.52	gold quality
male germ cell	CL:0000015	95.39	gold quality
choroid plexus epithelium	UBERON:0003911	94.61	gold quality
left testis	UBERON:0004533	94.57	gold quality
epithelium of nasopharynx	UBERON:0001951	94.56	gold quality
pituitary gland	UBERON:0000007	94.43	gold quality
right testis	UBERON:0004534	94.40	gold quality
adenohypophysis	UBERON:0002196	94.36	gold quality
nasal cavity epithelium	UBERON:0005384	93.02	gold quality
testis	UBERON:0000473	92.91	gold quality
germinal epithelium of ovary	UBERON:0001304	91.50	gold quality
trachea	UBERON:0003126	91.37	gold quality
left lobe of thyroid gland	UBERON:0001120	91.26	gold quality
nasal cavity mucosa	UBERON:0001826	91.15	gold quality
corpus epididymis	UBERON:0004359	91.09	gold quality
thyroid gland	UBERON:0002046	91.01	gold quality
upper leg skin	UBERON:0004262	90.88	gold quality
right lobe of thyroid gland	UBERON:0001119	90.80	gold quality
skin of hip	UBERON:0001554	90.14	gold quality
endometrium	UBERON:0001295	89.89	gold quality
nipple	UBERON:0002030	89.50	gold quality
endocervix	UBERON:0000458	89.49	gold quality
metanephros cortex	UBERON:0010533	88.94	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-HCAD-15	yes	1573.24
E-MTAB-10283	yes	1035.46
E-CURD-114	yes	898.48
E-HCAD-1	yes	28.03
E-MTAB-10287	yes	26.99
E-MTAB-9388	yes	7.44
E-CURD-89	no	123.11
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4, FOXJ1

miRNA regulators (miRDB)

115 targeting EFHC1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-5004-5P	99.68	66.63	1294

Literature-anchored findings (GeneRIF, showing 22)

• Mutation analyses identified five missense mutations in EFHC1 that cosegregated with epilepsy or EEG polyspike wave in affected members of six unrelated families with JME and did not occur in 382 control individuals (PMID:15258581)
• The combination of these polymorphisms could not be found in any control individuals, suggesting that they might be involved in genetic predisposition to migraine in this family. (PMID:16378686)
• Deletion analyses revealed that the N-terminal region of EFHC1 is crucial for the association with the mitotic spindle and the midbody. Our results suggest that EFHC1 could play an important role during cell division. (PMID:16824517)
• We found no evidence that EFHC1 is a major genetic risk factor for JME susceptibility in Dutch patients. (PMID:17054699)
• Mutations in the EFHC1 gene may underlie different types of epilepsy syndromes. (PMID:17159113)
• report presents one novel and one previously described mutation in the EFHC1 gene in Italian families, reinforcing the role of this gene in juvenile myoclonic epilepsy (PMID:17634063)
• In this case of juvenile myoclonic epilepsy, A molecular genetic analysis led to the identification of a polymorphism (A–>G) in position 10 in the intron 3 (rs949626) of the EFHC1 gene. (PMID:17972043)
• Nine percent of consecutive juvenile myoclonic epilepsy cases from Mexico and Honduras clinics and 3% of clinic patients from Japan carry mutations in Myoclonin1/EFCH1 (PMID:18505993)
• Under reducing condition Ca(2+) or Mg(2+) ions bind to EFHC1C in a 1/1 molar ratio, while under oxidizing condition this ratio is reduced, showing that EFHC1C dimerization blocks Ca(2+) and Mg(2+) binding (PMID:18593566)
• The results of this study show that four coding SNPs, rs3804506, rs3804505, rs1266787, and rs17851770, of EFHC1 may not be susceptibility alleles for juvenile myoclonic epilepsy. (PMID:18823326)
• The juvenile myoclonic epilepsy-related protein EFHC1 interacts with the redox-sensitive TRPM2 channel linked to cell death. (PMID:22226147)
• homozygous Phe229Leu mutation associated with primary intractable epilepsy in infancy (PMID:22690745)
• we conclude that mutations in the Myoclonin1/EFHC1 gene are an important cause of juvenile myoclonic epilepsy in Mexican patients. (PMID:22727576)
• These results show how Myoclonin1/EFHC1 mutations disrupt brain development and potentially produce structural brain abnormalities on which epileptogenesis is established. (PMID:22926142)
• Myoclonin1/EFHC1 mutation was suggested releated to juvenile myoclonic epilepsy. (PMID:23756480)
• Three SNP alleles in BRD2, Cx-36, and ME2 and microdeletions in 15q13.3, 15q11.2, and 16p13.11 also contribute risk to juvenile myclonic epilepsy. (PMID:23756481)
• some EFHC1 mutations may be pathogenic only when introduced into specific genetic backgrounds to juvenile myoclonic epilepsy (PMID:25489633)
• NHGRI gene-level evidence and variant-level evidence establish EFHC1 as the first non-ion channel microtubule-associated protein whose mutations disturb R-type VDCC and TRPM2 calcium currents in overgrown synapses and dendrites within abnormally migrated dislocated neurons, thus explaining CTC convulsions and “microdysgenesis” neuropathology of juvenile myoclonic epilepsy (PMID:27467453)
• EFHC1 mutations cause microtubule-associated defects in juvenile myoclonic epilepsy (PMID:28370826)
• Revisiting the clinical impact of variants in EFHC1 in patients with different phenotypes of genetic generalized epilepsy. (PMID:33181902)
• Mutational Analysis of Myoclonin1 Gene in Pakistani Juvenile Myoclonic Epilepsy Patients. (PMID:33969125)
• EFHC1 gene mutation profile of Turkish JME patients and its association with disease risk. (PMID:38088014)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	efhc1	ENSDARG00000009743
mus_musculus	Efhc1	ENSMUSG00000041809
rattus_norvegicus	Efhc1	ENSRNOG00000042729
caenorhabditis_elegans		WBGENE00013028

Paralogs (2): EFHB (ENSG00000163576), EFHC2 (ENSG00000183690)

Protein

Protein identifiers

EF-hand domain-containing protein 1 — Q5JVL4 (reviewed: Q5JVL4)

Alternative names: Myoclonin-1

All UniProt accessions (22): Q5JVL4, A0A1B0GTB1, A0A1B0GTD7, A0A1B0GTF7, A0A1B0GTH2, A0A1B0GTH7, A0A1B0GTM7, A0A1B0GTV4, A0A1B0GTV6, A0A1B0GTW5, A0A1B0GU13, A0A1B0GUE4, A0A1B0GUP6, A0A1B0GUV2, A0A1B0GV27, A0A1B0GVB0, A0A1B0GVP6, A0A1B0GVR3, A0A1B0GVZ5, A0A1B0GWB3, A0A1C7CYY1, B2CKC5

UniProt curated annotations — full annotation on UniProt →

Function. Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating. Microtubule-associated protein which regulates cell division and neuronal migration during cortical development. Necessary for radial and tangential cell migration during brain development, possibly acting as a regulator of cell morphology and process formation during migration. May enhance calcium influx through CACNA1E and stimulate programmed cell death.

Subunit / interactions. Microtubule inner protein component of sperm flagellar doublet microtubules. Interacts with the C-terminus of CACNA1E. Interacts with alpha-tubulin.

Subcellular location. Cytoplasm. Cytoskeleton. Cilium axoneme. Flagellum axoneme. Microtubule organizing center. Centrosome. Spindle. Spindle pole.

Tissue specificity. Widely expressed. Not detected in lymphocytes.

Disease relevance. Juvenile myoclonic epilepsy 1 (EJM1) [MIM:254770] A subtype of idiopathic generalized epilepsy. Patients have afebrile seizures only, with onset in adolescence (rather than in childhood) and myoclonic jerks which usually occur after awakening and are triggered by sleep deprivation and fatigue. Disease susceptibility is associated with variants affecting the gene represented in this entry. Juvenile absence epilepsy 1 (JAE1) [MIM:607631] A subtype of idiopathic generalized epilepsy characterized by onset occurring around puberty, absence seizures, generalized tonic-clonic seizures (GTCS), GTCS on awakening, and myoclonic seizures. Disease susceptibility is associated with variants affecting the gene represented in this entry. Mutation Leu-229 may be a cause of intractable epilepsy of infancy. Affected individuals have seizures of multiple type, manifested as tonic, clonic, and myoclonic seizures in the neonatal period, and as tonic seizures activated frequently by sleep, and repeated frequent myoclonic seizures in later infancy. The seizures are unresponsive to numerous antiepileptic drugs, and infants die in the first years of life. Although heterozygosity for Leu-229 has been associated with relatively benign forms of epilepsy in adolescence, homozygosity for the same mutation has much more severe consequences.

Miscellaneous. May be due to intron retention.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5JVL4-1	1	yes
Q5JVL4-2	2
Q5JVL4-3	3

RefSeq proteins (2): NP_001165891, NP_060570* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR006602	DM10_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR040193	EFHC1/EFHC2/EFHB	Family

Pfam: PF06565

UniProt features (44 total): sequence variant 31, domain 4, splice variant 3, sequence conflict 2, region of interest 2, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7UNG	ELECTRON MICROSCOPY	3.6
8J07	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5JVL4-F1	84.31	0.44

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 218 (showing top): GOBP_MITOTIC_CYTOKINESIS, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_FOREBRAIN_CELL_MIGRATION, ONKEN_UVEAL_MELANOMA_UP, chr6p12, WOO_LIVER_CANCER_RECURRENCE_UP, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, GOBP_CYTOKINESIS, GOBP_CEREBRAL_CORTEX_DEVELOPMENT, GOBP_CILIUM_MOVEMENT, GOCC_CENTROSOME, GOBP_PALLIUM_DEVELOPMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY

GO Biological Process (6): mitotic cytokinesis (GO:0000281), mitotic spindle organization (GO:0007052), cerebral cortex cell migration (GO:0021795), flagellated sperm motility (GO:0030317), regulation of cell division (GO:0051302), cilium-dependent cell motility (GO:0060285)

GO Molecular Function (3): calcium ion binding (GO:0005509), alpha-tubulin binding (GO:0043014), protein binding (GO:0005515)

GO Cellular Component (14): spindle pole (GO:0000922), centrosome (GO:0005813), axonemal microtubule (GO:0005879), axoneme (GO:0005930), sperm flagellum (GO:0036126), neuronal cell body (GO:0043025), mitotic spindle (GO:0072686), axonemal A tubule inner sheath (GO:0160111), cytoplasm (GO:0005737), spindle (GO:0005819), cytoskeleton (GO:0005856), cilium (GO:0005929), motile cilium (GO:0031514), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
mitotic cell cycle	2
spindle	2
intracellular membraneless organelle	2
cytoskeleton-dependent cytokinesis	1
mitotic cell cycle process	1
spindle organization	1
microtubule cytoskeleton organization involved in mitosis	1
cerebral cortex development	1
telencephalon cell migration	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
regulation of cellular process	1
cell division	1
cilium or flagellum-dependent cell motility	1
cilium movement	1
metal ion binding	1
tubulin binding	1
binding	1
centriole	1
microtubule organizing center	1
cytoplasmic microtubule	1
axoneme	1
cytoskeleton	1
microtubule	1
ciliary plasm	1
9+2 motile cilium	1
somatodendritic compartment	1
cell body	1
A axonemal microtubule	1
axonemal microtubule doublet inner sheath	1
intracellular anatomical structure	1
microtubule cytoskeleton	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cilium	1

Protein interactions and networks

STRING

2102 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EFHC1	CLCN2	P51788	922
EFHC1	PAQR8	Q8TEZ7	921
EFHC1	CACNB4	O00305	874
EFHC1	CACNA1E	Q15878	831
EFHC1	GABRD	O14764	819
EFHC1	GABRA1	P14867	812
EFHC1	BRD2	P25440	727
EFHC1	PACRG	Q96M98	583
EFHC1	DRC7	Q8IY82	518
EFHC1	SCN1A	P35498	510
EFHC1	CTSD	P07339	509
EFHC1	CILK1	Q9UPZ9	509
EFHC1	RSPH3	Q86UC2	497
EFHC1	MOB4	Q9Y3A3	482
EFHC1	ATP9A	O75110	480

IntAct

268 interactions, top by confidence:

A	B	Type	Score
IKZF3	EFHC1	psi-mi:“MI:0915”(physical association)	0.850
EFHC1	IKZF3	psi-mi:“MI:0915”(physical association)	0.850
EIF4ENIF1	EFHC1	psi-mi:“MI:0915”(physical association)	0.720
EFHC1	EIF4ENIF1	psi-mi:“MI:0915”(physical association)	0.720
EFHC1	KCTD4	psi-mi:“MI:0915”(physical association)	0.720
EFHC1	ZBED1	psi-mi:“MI:0915”(physical association)	0.720
EFHC1	EFHC2	psi-mi:“MI:0915”(physical association)	0.720
EFHC1	TEX11	psi-mi:“MI:0915”(physical association)	0.720
EFHC1	REL	psi-mi:“MI:0915”(physical association)	0.720
EFHC1	TCF4	psi-mi:“MI:0915”(physical association)	0.720
EFHC1	TRAF2	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (100): EFHC1 (Two-hybrid), EFHC1 (Two-hybrid), EFHC1 (Two-hybrid), EFHC1 (Two-hybrid), EFHC1 (Two-hybrid), EFHC1 (Two-hybrid), EFHC1 (Affinity Capture-MS), EFHC1 (Two-hybrid), EFHC1 (Synthetic Lethality), CCDC36 (Two-hybrid), EFHC2 (Two-hybrid), EIF4ENIF1 (Two-hybrid), GOLGA2 (Two-hybrid), HOMER3 (Two-hybrid), IKZF3 (Two-hybrid)

ESM2 similar proteins: A0A0G2K344, A0A3Q1N1R0, E1BKH1, G3GTP0, G5EF51, O13728, O70481, P06814, P16259, P16885, P20807, P24135, P32871, P34529, P35875, P42336, P42337, P43368, P49917, P51186, P97393, Q09879, Q11208, Q13017, Q32TF8, Q32TG3, Q4V8Q1, Q5JST6, Q5JVL4, Q5R6L3, Q64691, Q6GL75, Q6GQ76, Q6J756, Q6NU25, Q758X6, Q803R5, Q8BTF7, Q8BTI9, Q8CIH5

Diamond homologs: A0A3Q1N1R0, E1BKH1, Q32TF8, Q32TG3, Q5JST6, Q5JVL4, Q9D485, Q9D9T8, Q8N7U6, Q0IQB6, Q0IUU4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FOXJ1	“up-regulates quantity by expression”	EFHC1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	274
Likely benign	100
Benign	32

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
147421	GRCh38/hg38 6p12.2(chr6:51803422-52698500)x1	Pathogenic
205420	NM_018100.4(EFHC1):c.1314del (p.Phe438fs)	Pathogenic

SpliceAI

4771 predictions. Top by Δscore:

Variant	Effect	Δscore
6:52420465:GACTC:G	donor_gain	1.0000
6:52420471:ACGGT:A	donor_loss	1.0000
6:52420474:GTG:G	donor_loss	1.0000
6:52423944:A:AG	acceptor_gain	1.0000
6:52423945:G:GC	acceptor_gain	1.0000
6:52423945:GA:G	acceptor_gain	1.0000
6:52423945:GAA:G	acceptor_gain	1.0000
6:52423945:GAAA:G	acceptor_gain	1.0000
6:52423945:GAAAA:G	acceptor_gain	1.0000
6:52424060:GC:G	donor_gain	1.0000
6:52424069:GA:G	donor_gain	1.0000
6:52424070:A:G	donor_gain	1.0000
6:52424077:GGCCA:G	donor_gain	1.0000
6:52424078:GCCA:G	donor_gain	1.0000
6:52424078:GCCAG:G	donor_gain	1.0000
6:52424082:G:GG	donor_gain	1.0000
6:52438292:T:TA	acceptor_gain	1.0000
6:52438295:A:AG	acceptor_gain	1.0000
6:52438295:AT:A	acceptor_gain	1.0000
6:52438296:T:G	acceptor_gain	1.0000
6:52438296:T:TA	acceptor_gain	1.0000
6:52438301:TAGG:T	acceptor_loss	1.0000
6:52438303:GGT:G	acceptor_gain	1.0000
6:52438303:GGTA:G	acceptor_gain	1.0000
6:52438587:CACAG:C	donor_loss	1.0000
6:52438588:ACAGG:A	donor_loss	1.0000
6:52438589:CAG:C	donor_loss	1.0000
6:52438590:AG:A	donor_loss	1.0000
6:52438591:GG:G	donor_loss	1.0000
6:52438592:G:GA	donor_loss	1.0000

AlphaMissense

4240 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:52479064:C:A	R436S	0.993
6:52479065:G:C	R436P	0.993
6:52469457:G:C	R421P	0.991
6:52438511:T:A	W165R	0.990
6:52438511:T:C	W165R	0.990
6:52479117:G:C	E453D	0.990
6:52479117:G:T	E453D	0.990
6:52438308:T:C	L97P	0.989
6:52454099:T:C	L243P	0.989
6:52438371:G:C	R118P	0.988
6:52454102:G:C	R244P	0.987
6:52454104:T:C	F245L	0.987
6:52454106:C:A	F245L	0.987
6:52454106:C:G	F245L	0.987
6:52479070:T:C	F438L	0.987
6:52479072:T:A	F438L	0.987
6:52479072:T:G	F438L	0.987
6:52479110:T:A	I451N	0.987
6:52479655:T:C	F503S	0.987
6:52479071:T:C	F438S	0.986
6:52469454:T:C	L420P	0.985
6:52469466:C:A	A424D	0.985
6:52454111:C:A	A247E	0.984
6:52479654:T:C	F503L	0.983
6:52479656:C:A	F503L	0.983
6:52479656:C:G	F503L	0.983
6:52469459:T:G	Y422D	0.981
6:52479064:C:G	R436G	0.979
6:52438313:T:C	F99L	0.978
6:52438314:T:C	F99S	0.978

dbSNP variants (sampled 300 via entrez): RS1000022850 (6:52480258 T>A,G), RS1000052719 (6:52433109 A>G), RS1000055431 (6:52459516 G>A,T), RS1000063478 (6:52491645 C>T), RS1000066665 (6:52466043 T>C), RS1000071974 (6:52440183 C>A,G), RS1000126768 (6:52456382 C>T), RS1000153411 (6:52441347 A>C,G), RS1000204848 (6:52488165 G>T), RS1000208842 (6:52481068 C>G,T), RS1000305208 (6:52439450 G>C), RS1000318518 (6:52430115 T>C), RS1000373783 (6:52443720 G>A,C), RS1000397220 (6:52418503 T>C), RS1000434287 (6:52487911 T>C)

Disease associations

OMIM: gene MIM:608815 | disease phenotypes: MIM:254770, MIM:606904, MIM:604827, MIM:607631

GenCC curated gene-disease

Disease	Classification	Inheritance
juvenile myoclonic epilepsy	Limited	Autosomal dominant
epilepsy	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
epilepsy	Refuted	AD

Mondo (5): myoclonic epilepsy, juvenile, susceptibility to, 1 (MONDO:0020752), juvenile myoclonic epilepsy (MONDO:0009696), epilepsy, idiopathic generalized, susceptibility to, 7 (MONDO:0011491), epilepsy, juvenile absence, susceptibility to, 1 (MONDO:0020772), epilepsy (MONDO:0005027)

Orphanet (2): Juvenile absence epilepsy (Orphanet:1941), Juvenile myoclonic epilepsy (Orphanet:307)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000153	Abnormality of the mouth
HP:0000496	Abnormality of eye movement
HP:0000718	Aggressive behavior
HP:0000739	Anxiety
HP:0001249	Intellectual disability
HP:0001328	Specific learning disability
HP:0001336	Myoclonus
HP:0002069	Bilateral tonic-clonic seizure
HP:0002121	Generalized non-motor (absence) seizure
HP:0002123	Generalized myoclonic seizure
HP:0002133	Status epilepticus
HP:0002197	Generalized-onset seizure
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002392	EEG with polyspike wave complexes
HP:0003621	Juvenile onset
HP:0007000	Morning myoclonic jerks
HP:0007193	Bilateral tonic-clonic seizure on awakening
HP:0007207	Photosensitive tonic-clonic seizure
HP:0010849	EEG with spike-wave complexes (>3.5 Hz)
HP:0012001	EEG with generalized polyspikes
HP:0032794	Myoclonic seizure
HP:0100851	Abnormal emotional state

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST003180_2	Atopic march	2.000000e-08
GCST003265_212	Post bronchodilator FEV1/FVC ratio in COPD	2.000000e-06
GCST004599_230	Mean platelet volume	2.000000e-16
GCST008769_4	Perceived intensity of glucose	2.000000e-06
GCST009817_2	Clozapine-induced myocarditis in schizophrenia	8.000000e-07
GCST90002407_266	White blood cell count	4.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007755	atopic march
EFO:0004713	FEV/FVC ratio

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D020190	Myoclonic Epilepsy, Juvenile	C10.228.140.490.375.130.670; C10.228.140.490.493.063.670

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

46 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	4
trichostatin A	affects cotreatment, decreases expression	3
Air Pollutants	decreases expression, affects cotreatment, affects expression, increases abundance, increases expression	3
bisphenol A	increases methylation, affects cotreatment, affects methylation, decreases expression, decreases methylation	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Nickel	decreases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, affects expression, increases abundance	1
beta-lapachone	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
nickel sulfate	increases expression	1
methacrylaldehyde	affects cotreatment, affects expression, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, affects methylation, increases methylation	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, affects expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Demecolcine	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	PHASE4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	PHASE4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy