SCN4A
sodium voltage-gated channel alpha subunit 4, the group of Sodium voltage-gated channel alpha subunits
Basic information
Region (hg38): 17:63938554-63972918
Previous symbols: [ "HYKPP" ]
Links
Phenotypes
GenCC
Source:
- hyperkalemic periodic paralysis (Definitive), mode of inheritance: AD
- paramyotonia congenita of Von Eulenburg (Definitive), mode of inheritance: AD
- congenital myasthenic syndrome 16 (Strong), mode of inheritance: AR
- hypokalemic periodic paralysis, type 2 (Strong), mode of inheritance: AD
- hyperkalemic periodic paralysis (Strong), mode of inheritance: AD
- paramyotonia congenita of Von Eulenburg (Strong), mode of inheritance: AD
- congenital myopathy (Strong), mode of inheritance: AR
- congenital myasthenic syndrome 16 (Strong), mode of inheritance: AR
- paramyotonia congenita of Von Eulenburg (Definitive), mode of inheritance: AD
- paramyotonia congenita of Von Eulenburg (Supportive), mode of inheritance: AD
- hypokalemic periodic paralysis (Supportive), mode of inheritance: AD
- hyperkalemic periodic paralysis (Supportive), mode of inheritance: AD
- postsynaptic congenital myasthenic syndrome (Supportive), mode of inheritance: AR
- myotonia fluctuans (Supportive), mode of inheritance: AD
- myotonia permanens (Supportive), mode of inheritance: AD
- acetazolamide-responsive myotonia (Supportive), mode of inheritance: AD
- congenital myasthenic syndrome 16 (Strong), mode of inheritance: AR
- SCN4A-related myopathy, autosomal recessive (Definitive), mode of inheritance: AR
- potassium-aggravated myotonia (Strong), mode of inheritance: AD
- congenital myasthenic syndrome 16 (Limited), mode of inheritance: AR
- hypokalemic periodic paralysis, type 2 (Strong), mode of inheritance: AD
- hyperkalemic periodic paralysis (Strong), mode of inheritance: AD
- paramyotonia congenita of Von Eulenburg (Strong), mode of inheritance: AD
- congenital myopathy 22A, classic (Strong), mode of inheritance: AR
- SCN4A-related myopathy, autosomal recessive (Definitive), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Paramyotonia congenita; Hyperkalemic periodic paralysis, type 2; Hypokalemic periodic paralysis, type 2; Normokalemic potassium-sensitive periodic paralysis; Malignant hyperthermia, susceptibility to; Myasthenic syndrome, congenital, 16; Myotonia, potassium-aggravated | AD/AR | Cardiovascular; Musculoskeletal; Neurologic; Pharmacogenomic | In hypokalemic disease, treatment, such as potassium supplementation can be effective; Acetazolamide treatment is beneficial in the majority (including with normokalemic and hyperkalemic disease), but in a lower proportion of variant-negative patients; Individuals can have cardiac complications, including sudden cardiac death; In Paramyotonia congenita, medications (eg, mexilitene, carbamazepine, phenytoin) may be effect in some individuals, and avoidance and specific preciptating circumstances may be beneficial; Myotonia, potassium-aggravated can be aggravated by potassium and fasting, and effectively treated with medications (eg, acetazolamide, carbamazepine, mexilitene); In Malignant hyperthermia, early diagnosis, discontinuation of potent inhalation agents/succinylcholine, treatment of metabolic abnormalities, and administration of dantrolene sodium intravenously are essential to treat acute MH; In Myasthenic syndrome, congenital, pyridostigmine can improve endurance; Acetazolamide can prevent further attacks of respiratory and bulbar weakness | Cardiovascular; Craniofacial; Musculoskeletal; Neurologic | 13544644; 13758355; 13963901; 13946346; 14090531; 5828532; 14237771; 673408; 852462; 4022357; 3587272; 2396930; 1654742; 1310898; 1338909; 1316765; 8424309; 8385748; 8242056; 8308722; 8058156; 7741283; 9131651; 9131654; 10599760; 10369308; 10930446; 10727489; 12933953; 12766226; 15534250; 15557532; 15596759; 15642860; 16832098; 16786525; 17998485; 18203179; 19015492; 19015483; 18337100; 19118277; 20237798; 20301512; 20301669; 20713951; 21220685; 22617007; 23460624; 23516313; 23771340; 23801527; 23958773; 24082935; 25707578; 26659129; 26700687; 28262468; 36090556 |
| Clinically, allelic conditions have been divided into different forms of the disorder: paramyotonia, potassium-aggravated myotonia, and periodic paralysis; Potassium-aggravated myotonia includes mild myotonia fluctuans, severe myotonia permanens, and acetazolamide-responsive myotonia |
ClinVar
This is a list of variants' phenotypes submitted to
- Hyperkalemic_periodic_paralysis (1826 variants)
- not_provided (750 variants)
- Paramyotonia_congenita_of_Von_Eulenburg (551 variants)
- Hypokalemic_periodic_paralysis,_type_2 (541 variants)
- Congenital_myasthenic_syndrome_16 (535 variants)
- Potassium-aggravated_myotonia (532 variants)
- Congenital_myopathy_22B,_severe_fetal (265 variants)
- Congenital_myopathy_22A,_classic (265 variants)
- Inborn_genetic_diseases (186 variants)
- Hypokalemic_periodic_paralysis,_type_1 (174 variants)
- not_specified (162 variants)
- SCN4A-related_disorder (62 variants)
- SCN4A-related_non-dystrophic_myotonia (17 variants)
- SCN4A-related_myopathy,_autosomal_recessive (7 variants)
- Paramyotonia_congenita/hyperkalemic_periodic_paralysis (4 variants)
- Normokalemic_periodic_paralysis,_potassium-sensitive (3 variants)
- Congenital_myasthenic_syndrome (3 variants)
- Long_QT_syndrome (2 variants)
- Microcephaly (2 variants)
- See_cases (2 variants)
- Myotonia_fluctuans (2 variants)
- Myotonia (2 variants)
- Limb-girdle_muscular_dystrophy (2 variants)
- Acetazolamide-responsive_myotonia (2 variants)
- Myopathy (2 variants)
- Skeletal_myopathy (1 variants)
- Batten-Turner_congenital_myopathy (1 variants)
- Tremor,_hereditary_essential,_6 (1 variants)
- Severe_neonatal_hypotonia_improving_with_age (1 variants)
- Sotos_syndrome (1 variants)
- Joubert_syndrome_17 (1 variants)
- Abnormality_of_the_musculature (1 variants)
- Delayed_gross_motor_development (1 variants)
- Handgrip_myotonia (1 variants)
- Congenital_myopathy (1 variants)
- Distal_sensory_impairment (1 variants)
- Neuromuscular_disease (1 variants)
- Myotonia_congenita,_atypical,_acetazolamide-responsive (1 variants)
- Rhabdomyolysis (1 variants)
- Muscular_channelopathy (1 variants)
- Paramyotonia_congenita/myotonia_congenita (1 variants)
- Hypokalemic_periodic_paralysis (1 variants)
- Pain (1 variants)
- EMG:_myotonic_discharges (1 variants)
- Arthrogryposis_multiplex_congenita (1 variants)
- Muscle_weakness (1 variants)
- Limb_pain (1 variants)
- Skeletal_muscle_channelopathy (1 variants)
- Focal-onset_seizure (1 variants)
- SCN4A-related_channelopathy (1 variants)
- Congenital_myotonia,_autosomal_dominant_form (1 variants)
- Fetal_akinesia_deformation_sequence_1 (1 variants)
- SUDDEN_INFANT_DEATH_SYNDROME (1 variants)
- Myotonia_permanens (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the SCN4A gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000334.4. Only rare variants are included in the table.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUSVUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 28 | 443 | 24 | 495 | ||
| missense | 43 | 85 | 1100 | 69 | 1303 | |
| nonsense | 11 | 10 | 24 | |||
| start loss | 0 | |||||
| frameshift | 12 | 11 | 28 | |||
| splice donor/acceptor (+/-2bp) | 11 | |||||
| Total | 67 | 114 | 1138 | 512 | 30 |
Highest pathogenic variant AF is 0.0005239833
Loading clinvar variants...
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| SCN4A | protein_coding | protein_coding | ENST00000435607 | 24 | 34365 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.0129 | 0.987 | 125436 | 0 | 310 | 125746 | 0.00123 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 1.56 | 977 | 1.12e+3 | 0.869 | 0.0000707 | 12161 |
| Missense in Polyphen | 327 | 465.98 | 0.70175 | 5051 | ||
| Synonymous | 0.105 | 480 | 483 | 0.994 | 0.0000355 | 3468 |
| Loss of Function | 5.91 | 19 | 73.7 | 0.258 | 0.00000357 | 806 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.0102 | 0.00858 |
| Ashkenazi Jewish | 0.000656 | 0.000595 |
| East Asian | 0.000855 | 0.000653 |
| Finnish | 0.000582 | 0.000554 |
| European (Non-Finnish) | 0.000768 | 0.000703 |
| Middle Eastern | 0.000855 | 0.000653 |
| South Asian | 0.00135 | 0.00118 |
| Other | 0.000782 | 0.000652 |
dbNSFP
Source:
- Function
- FUNCTION: This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. This sodium channel may be present in both denervated and innervated skeletal muscle. {ECO:0000269|PubMed:15318338, ECO:0000269|PubMed:16890191}.;
- Disease
- DISEASE: Paramyotonia congenita of von Eulenburg (PMC) [MIM:168300]: An autosomal dominant channelopathy characterized by myotonia, increased by exposure to cold, intermittent flaccid paresis, not necessarily dependent on cold or myotonia, lability of serum potassium, non-progressive nature and lack of atrophy or hypertrophy of muscles. In some patients, myotonia is not increased by cold exposure (paramyotonia without cold paralysis). Patients may have a combination phenotype of PMC and HYPP. {ECO:0000269|PubMed:10369308, ECO:0000269|PubMed:10727489, ECO:0000269|PubMed:1310898, ECO:0000269|PubMed:1316765, ECO:0000269|PubMed:1338909, ECO:0000269|PubMed:15318338, ECO:0000269|PubMed:15790667, ECO:0000269|PubMed:16786525, ECO:0000269|PubMed:18166706, ECO:0000269|PubMed:18690054, ECO:0000269|PubMed:19077043, ECO:0000269|PubMed:20076800, ECO:0000269|PubMed:8242056, ECO:0000269|PubMed:8308722, ECO:0000269|PubMed:8388676, ECO:0000269|PubMed:8580427}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Periodic paralysis hypokalemic 2 (HOKPP2) [MIM:613345]: An autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels. {ECO:0000269|PubMed:10599760, ECO:0000269|PubMed:10851391, ECO:0000269|PubMed:10944223, ECO:0000269|PubMed:11558801, ECO:0000269|PubMed:11591859, ECO:0000269|PubMed:16890191, ECO:0000269|PubMed:17898326, ECO:0000269|PubMed:18162704, ECO:0000269|PubMed:19118277, ECO:0000269|PubMed:20522878, ECO:0000269|PubMed:21043388, ECO:0000269|PubMed:24549961}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Periodic paralysis hyperkalemic (HYPP) [MIM:170500]: An autosomal dominant channelopathy characterized by episodic flaccid generalized muscle weakness associated with high levels of serum potassium. Concurrence of myotonia is found in HYPP patients. {ECO:0000269|PubMed:1659668, ECO:0000269|PubMed:1659948, ECO:0000269|PubMed:20076800}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Periodic paralysis normokalemic (NKPP) [MIM:170500]: A disorder closely related to hyperkalemic periodic paralysis, but marked by a lack of alterations in potassium levels during attacks of muscle weakness. {ECO:0000269|PubMed:15596759, ECO:0000269|PubMed:18046642, ECO:0000269|PubMed:20522878}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myotonia SCN4A-related (MYOSCN4A) [MIM:608390]: A phenotypically highly variable myotonia aggravated by potassium loading, and sometimes by cold. Myotonia is characterized by sustained muscle tensing that prevents muscles from relaxing normally. It causes muscle stiffness that can interfere with movement. In some people the stiffness is very mild, while in other cases it may be severe enough to interfere with walking, running, and other activities of daily life. Myotonia SCN4A- related includes myotonia permanens and myotonia fluctuans. In myotonia permanens, the myotonia is generalized and there is a hypertrophy of the muscle, particularly in the neck and the shoulder. Attacks of severe muscle stiffness of the thoracic muscles may be life threatening due to impaired ventilation. In myotonia fluctuans, the muscle stiffness may fluctuate from day to day, provoked by exercise. {ECO:0000269|PubMed:10218481, ECO:0000269|PubMed:16786525, ECO:0000269|PubMed:16832098, ECO:0000269|PubMed:17212350, ECO:0000269|PubMed:17998485, ECO:0000269|PubMed:18203179, ECO:0000269|PubMed:18337100, ECO:0000269|PubMed:19015483, ECO:0000269|PubMed:19347921, ECO:0000269|PubMed:20076800, ECO:0000269|PubMed:27653901, ECO:0000269|PubMed:8058156, ECO:0000269|PubMed:9392583}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myasthenic syndrome, congenital, 16 (CMS16) [MIM:614198]: 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. CMS16 is characterized by fatigable generalized weakness and recurrent attacks of respiratory and bulbar paralysis since birth. The fatigable weakness involves lid-elevator, external ocular, facial, limb and truncal muscles and an decremental response of the compound muscle action potential on repetitive stimulation. {ECO:0000269|PubMed:12766226, ECO:0000269|PubMed:25707578, ECO:0000269|PubMed:26659129}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=SCN4A mutations are the cause of an autosomal recessive neuromuscular disorder characterized by severe fetal hypokinesia, neonatal hypotonia and congenital myopathy of variable severity. The most severe clinical features include reduced or absent fetal movements, in-utero upper and lower limb contractures, talipes and hydrops, and intrauterine or early postnatal death. Mildly affected patients present with generalized hypotonia and weakness at birth or within the first few days of life, mild-to-moderate facial muscle weakness without ptosis, significant early respiratory and feeding difficulties, and skeletal abnormalities of the spine and palate. Symptoms improve over time in patients who survive infancy, resulting in gain of muscle strength and motor skills and concomitant resolution of early respiratory and feeding difficulties. In contrast to other SCN4A-related channelopathies, affected individuals manifest in- utero or neonatal onset of permanent muscle weakness, rather than later-onset episodic muscle weakness. {ECO:0000269|PubMed:26700687}.;
- Pathway
- Developmental Biology;Phase 0 - rapid depolarisation;Cardiac conduction;Muscle contraction;Interaction between L1 and Ankyrins;L1CAM interactions;Axon guidance
(Consensus)
Recessive Scores
- pRec
- 0.338
Intolerance Scores
- loftool
- 0.00572
- rvis_EVS
- -0.75
- rvis_percentile_EVS
- 13.68
Haploinsufficiency Scores
- pHI
- 0.132
- hipred
- Y
- hipred_score
- 0.554
- ghis
- 0.512
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.794
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Scn4a
- Phenotype
- muscle phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hearing/vestibular/ear phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan);
Zebrafish Information Network
- Gene name
- scn4aa
- Affected structure
- skeletal muscle
- Phenotype tag
- abnormal
- Phenotype quality
- disorganized
Gene ontology
- Biological process
- sodium ion transport;muscle contraction;neuronal action potential;regulation of ion transmembrane transport;sodium ion transmembrane transport;membrane depolarization during action potential
- Cellular component
- voltage-gated sodium channel complex;plasma membrane;integral component of plasma membrane;axon
- Molecular function
- voltage-gated ion channel activity;voltage-gated sodium channel activity