HCN4
hyperpolarization activated cyclic nucleotide gated potassium channel 4, the group of Cyclic nucleotide gated channels
Basic information
Region (hg38): 15:73319859-73368958
Links
Phenotypes
GenCC
Source:
- Brugada syndrome 8 (Limited), mode of inheritance: AD
- sick sinus syndrome 2, autosomal dominant (Strong), mode of inheritance: AD
- Brugada syndrome 8 (Moderate), mode of inheritance: AD
- sick sinus syndrome 2, autosomal dominant (Strong), mode of inheritance: AD
- familial sick sinus syndrome (Supportive), mode of inheritance: AD
- Brugada syndrome 8 (Limited), mode of inheritance: AD
- sick sinus syndrome 2, autosomal dominant (Strong), mode of inheritance: AD
- Brugada syndrome 1 (Disputed Evidence), mode of inheritance: AD
- familial thoracic aortic aneurysm and aortic dissection (Limited), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Brugada syndrome 8; Sick sinus syndrome 2 | AD | Cardiovascular; Neurologic | Variants may result in several cardiac conditions involving arrhythmia, and, depending on the condition, surveillance with approximately yearly EKG and medical interventions, including daily quinidine for prevention (though treatment of asymptomatic individuals is controversial), ICD placement in individuals with previous cardiac arrest/syncope, and isoproterenol for electrical storms, may be beneficial; Certain agents should be avoided, including medications such as certain anesthetics, antidepressants, and antipsychotics, and care should be taken in the instance of high fever | Cardiovascular | 8750801; 12750403; 15123648; 16407510; 17646576; 19165230; 20301690; 29588962; 30127718 |
ClinVar
This is a list of variants' phenotypes submitted to
- Brugada_syndrome_8 (1627 variants)
- Cardiovascular_phenotype (979 variants)
- not_provided (320 variants)
- not_specified (135 variants)
- Sick_sinus_syndrome_2,_autosomal_dominant (134 variants)
- Epilepsy,_idiopathic_generalized,_susceptibility_to,_18 (79 variants)
- HCN4-related_disorder (46 variants)
- Cardiomyopathy (7 variants)
- Hypertrophic_cardiomyopathy (4 variants)
- Left_ventricular_noncompaction_cardiomyopathy (4 variants)
- Ventricular_tachycardia (4 variants)
- Brugada_syndrome (3 variants)
- Atrial_fibrillation (2 variants)
- Left_ventricular_noncompaction (2 variants)
- Long_QT_syndrome (2 variants)
- Sudden_cardiac_death (2 variants)
- Primary_dilated_cardiomyopathy (2 variants)
- Congestive_heart_failure (1 variants)
- Sinus_bradycardia (1 variants)
- Sinoatrial_node_disorder (1 variants)
- Inborn_genetic_diseases (1 variants)
- Cardiac_arrhythmia (1 variants)
- Arrhythmogenic_right_ventricular_cardiomyopathy (1 variants)
- Cardiac_arrest (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the HCN4 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000005477.3. 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 | 684 | 11 | 701 | |||
| missense | 12 | 1012 | 67 | 1100 | ||
| nonsense | 11 | 11 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 40 | 43 | ||||
| splice donor/acceptor (+/-2bp) | 6 | |||||
| Total | 8 | 14 | 1075 | 751 | 14 |
Highest pathogenic variant AF is 0.0000065698705
Loading clinvar variants...
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| HCN4 | protein_coding | protein_coding | ENST00000261917 | 8 | 49406 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.999 | 0.00133 | 125705 | 0 | 42 | 125747 | 0.000167 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 2.75 | 478 | 679 | 0.703 | 0.0000452 | 7601 |
| Missense in Polyphen | 55 | 54.848 | 1.0028 | 620 | ||
| Synonymous | 0.629 | 296 | 310 | 0.955 | 0.0000217 | 2652 |
| Loss of Function | 4.79 | 3 | 32.5 | 0.0924 | 0.00000162 | 362 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000419 | 0.000391 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.000166 | 0.000163 |
| Finnish | 0.0000924 | 0.0000924 |
| European (Non-Finnish) | 0.000195 | 0.000185 |
| Middle Eastern | 0.000166 | 0.000163 |
| South Asian | 0.000133 | 0.000131 |
| Other | 0.000341 | 0.000326 |
dbNSFP
Source:
- Function
- FUNCTION: Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) that regulate the rhythm of heart beat. May contribute to the native pacemaker currents in neurons (Ih). May mediate responses to sour stimuli. {ECO:0000269|PubMed:10228147, ECO:0000269|PubMed:10430953, ECO:0000269|PubMed:16407510, ECO:0000269|PubMed:19165230, ECO:0000269|PubMed:20829353}.;
- Disease
- DISEASE: Sick sinus syndrome 2 (SSS2) [MIM:163800]: The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS2 onset is in utero or at birth. {ECO:0000269|PubMed:15123648, ECO:0000269|PubMed:16407510, ECO:0000269|PubMed:20662977, ECO:0000269|PubMed:23103389}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Brugada syndrome 8 (BRGDA8) [MIM:613123]: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. {ECO:0000269|PubMed:19165230}. Note=The gene represented in this entry may be involved in disease pathogenesis.;
- Pathway
- cAMP signaling pathway - Homo sapiens (human);Taste transduction - Homo sapiens (human);Antiarrhythmic Pathway, Pharmacodynamics;Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;TarBasePathway;Neuronal System;HCN channels;Potassium Channels
(Consensus)
Recessive Scores
- pRec
- 0.140
Haploinsufficiency Scores
- pHI
- 0.257
- hipred
- Y
- hipred_score
- 0.771
- ghis
- 0.439
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.836
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Hcn4
- Phenotype
- muscle phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); normal 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);
Zebrafish Information Network
- Gene name
- hcn4
- Affected structure
- heart contraction
- Phenotype tag
- abnormal
- Phenotype quality
- decreased rate
Gene ontology
- Biological process
- regulation of heart rate;regulation of membrane depolarization;cation transport;muscle contraction;blood circulation;regulation of ion transmembrane transport;sodium ion transmembrane transport;regulation of membrane potential;regulation of cardiac muscle contraction;cellular response to cAMP;cellular response to cGMP;potassium ion transmembrane transport;membrane depolarization during cardiac muscle cell action potential;SA node cell action potential;membrane depolarization during SA node cell action potential;regulation of heart rate by cardiac conduction;sodium ion import across plasma membrane;regulation of cardiac muscle cell action potential involved in regulation of contraction;potassium ion import across plasma membrane
- Cellular component
- plasma membrane;intrinsic component of plasma membrane;perinuclear region of cytoplasm;HCN channel complex
- Molecular function
- intracellular cAMP-activated cation channel activity;voltage-gated sodium channel activity;voltage-gated potassium channel activity;cAMP binding;identical protein binding;voltage-gated potassium channel activity involved in SA node cell action potential depolarization