HCN4

hyperpolarization activated cyclic nucleotide gated potassium channel 4, the group of Cyclic nucleotide gated channels

Basic information

Region (hg38): 15:73319858-73368958

Links

ENSG00000138622 ∙ NCBI:10021 ∙ OMIM:605206 ∙ HGNC:16882 ∙ Uniprot:Q9Y3Q4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 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: CGD

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 ClinVar and linked to the HCN4 gene.

• Brugada syndrome 8 (1197 variants)
• Cardiovascular phenotype (573 variants)
• not provided (265 variants)
• not specified (93 variants)
• Sick sinus syndrome 2, autosomal dominant (86 variants)
• Inborn genetic diseases (18 variants)
• Brugada syndrome 8;Sick sinus syndrome 2, autosomal dominant;Epilepsy, idiopathic generalized, susceptibility to, 18 (17 variants)
• Sick sinus syndrome 2, autosomal dominant;Brugada syndrome 8;Epilepsy, idiopathic generalized, susceptibility to, 18 (17 variants)
• Epilepsy, idiopathic generalized, susceptibility to, 18;Sick sinus syndrome 2, autosomal dominant;Brugada syndrome 8 (13 variants)
• Brugada syndrome 8;Epilepsy, idiopathic generalized, susceptibility to, 18;Sick sinus syndrome 2, autosomal dominant (12 variants)
• HCN4-related condition (11 variants)
• Sick sinus syndrome 2, autosomal dominant;Epilepsy, idiopathic generalized, susceptibility to, 18;Brugada syndrome 8 (9 variants)
• Cardiomyopathy (5 variants)
• Epilepsy, idiopathic generalized, susceptibility to, 18;Brugada syndrome 8;Sick sinus syndrome 2, autosomal dominant (4 variants)
• Brugada syndrome 8;Sick sinus syndrome 2, autosomal dominant (4 variants)
• Ventricular tachycardia (3 variants)
• Sick sinus syndrome 2, autosomal dominant;Brugada syndrome 8 (3 variants)
• Hypertrophic cardiomyopathy (3 variants)
• Left ventricular noncompaction cardiomyopathy (3 variants)
• Long QT syndrome (2 variants)
• Brugada syndrome (2 variants)
• Cardiac arrhythmia (1 variants)
• Arrhythmogenic right ventricular cardiomyopathy (1 variants)
• Congestive heart failure (1 variants)
• Sinus node disease (1 variants)
• Sudden cardiac death;Sinus bradycardia (1 variants)
• Left ventricular noncompaction (1 variants)
• Epilepsy, idiopathic generalized, susceptibility to, 18 (1 variants)
• Atrial fibrillation (1 variants)
• Cardiac arrest (1 variants)
• Primary dilated cardiomyopathy (1 variants)
• Primary dilated cardiomyopathy;Cardiomyopathy (1 variants)
• Sudden cardiac death (1 variants)
• HCN4-related disorder (1 variants)
• Sick sinus syndrome 2, autosomal dominant;Epilepsy, idiopathic generalized, susceptibility to, 18 (1 variants)
• Ventricular tachycardia;Atrial fibrillation;Cardiomyopathy;Hypertrophic cardiomyopathy (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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			12	437	14	463
missense	1	11	726	21	2	761
nonsense			8			8
start loss			1			1
frameshift			28			28
inframe indel			21			21
splice donor/acceptor (+/-2bp)		1	4			5
splice region			10	17	1	28
non coding			28	58	27	113
Total	1	12	828	516	43

Highest pathogenic variant AF is 0.00000657

Variants in HCN4

This is a list of pathogenic ClinVar variants found in the HCN4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
15-73319896-C-T		Sick sinus syndrome 2, autosomal dominant	Uncertain significance (Jan 13, 2018)
15-73319900-G-A		Sick sinus syndrome 2, autosomal dominant	Benign (Sep 01, 2022)
15-73320036-G-A		Sick sinus syndrome 2, autosomal dominant	Benign (Jan 13, 2018)
15-73320088-G-C		Sick sinus syndrome 2, autosomal dominant	Benign (Jan 13, 2018)
15-73320127-T-C		Sick sinus syndrome 2, autosomal dominant	Benign (Jan 13, 2018)
15-73320240-A-G		Sick sinus syndrome 2, autosomal dominant	Uncertain significance (Jan 13, 2018)
15-73320471-T-G		Sick sinus syndrome 2, autosomal dominant	Uncertain significance (Jan 13, 2018)
15-73320492-C-T		Sick sinus syndrome 2, autosomal dominant	Benign (Jan 13, 2018)
15-73320647-C-A		Sick sinus syndrome 2, autosomal dominant	Uncertain significance (Jan 13, 2018)
15-73320822-T-C		Sick sinus syndrome 2, autosomal dominant	Benign (Jan 13, 2018)
15-73320883-T-C		Sick sinus syndrome 2, autosomal dominant • Epilepsy, idiopathic generalized, susceptibility to, 18;Brugada syndrome 8;Sick sinus syndrome 2, autosomal dominant	Uncertain significance (Dec 27, 2021)
15-73320991-T-G		Sick sinus syndrome 2, autosomal dominant	Benign (Jan 13, 2018)
15-73320999-T-C		Sick sinus syndrome 2, autosomal dominant	Benign (Jan 13, 2018)
15-73321276-T-C		Sick sinus syndrome 2, autosomal dominant	Uncertain significance (Jan 15, 2018)
15-73321284-A-G		Sick sinus syndrome 2, autosomal dominant	Benign (Jan 13, 2018)
15-73321309-T-C		Sick sinus syndrome 2, autosomal dominant	Uncertain significance (Jan 13, 2018)
15-73321341-C-T		Sick sinus syndrome 2, autosomal dominant	Benign (Jan 13, 2018)
15-73321396-T-G		Sick sinus syndrome 2, autosomal dominant	Conflicting classifications of pathogenicity (Jul 01, 2022)
15-73321501-G-A		Sick sinus syndrome 2, autosomal dominant	Uncertain significance (Jan 13, 2018)
15-73321580-G-A		Sick sinus syndrome 2, autosomal dominant	Uncertain significance (Jan 13, 2018)
15-73321634-T-C		Sick sinus syndrome 2, autosomal dominant	Uncertain significance (Jan 12, 2018)
15-73321637-C-T		Sick sinus syndrome 2, autosomal dominant	Benign (Jan 13, 2018)
15-73321714-G-A		Sick sinus syndrome 2, autosomal dominant	Uncertain significance (Jan 12, 2018)
15-73321773-T-C		Sick sinus syndrome 2, autosomal dominant	Benign (Jan 13, 2018)
15-73321847-G-A		Sick sinus syndrome 2, autosomal dominant	Benign (Jan 13, 2018)

GnomAD

Source: gnomAD

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: dbNSFP

• 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