HCN1

hyperpolarization activated cyclic nucleotide gated potassium channel 1, the group of Cyclic nucleotide gated channels

Basic information

Region (hg38): 5:45254948-45696498

Previous symbols: [ "BCNG1" ]

Links

ENSG00000164588 ∙ NCBI:348980 ∙ OMIM:602780 ∙ HGNC:4845 ∙ Uniprot:O60741 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• developmental and epileptic encephalopathy, 24 (Definitive), mode of inheritance: AD
• developmental and epileptic encephalopathy, 24 (Definitive), mode of inheritance: AD
• generalized epilepsy with febrile seizures plus (Supportive), mode of inheritance: AD
• undetermined early-onset epileptic encephalopathy (Supportive), mode of inheritance: AD
• developmental and epileptic encephalopathy, 24 (Strong), mode of inheritance: AD
• generalized epilepsy with febrile seizures plus, type 10 (Strong), mode of inheritance: AD
• generalized epilepsy with febrile seizures plus (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental and epileptic encephalopathy 24; Generalized epilepsy with febrile seizures plus, type 10	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	24747641; 29936235; 30351409
As with other forms of epilepsy, optimal seizure control is advantageous, and genetic diagnosis may aid with medication selection

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HCN1 gene.

• Early infantile epileptic encephalopathy with suppression bursts (6 variants)
• Developmental and epileptic encephalopathy, 24 (3 variants)
• Generalized epilepsy with febrile seizures plus, type 10 (2 variants)
• not provided (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HCN1 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			6	235	4	245
missense	8	18	336	53	2	417
nonsense			12			12
start loss			2			2
frameshift		1	14			15
inframe indel			21	6	1	28
splice donor/acceptor (+/-2bp)			4			4
splice region			8	18	1	27
non coding			4	64	13	81
Total	8	19	399	358	20

Variants in HCN1

This is a list of pathogenic ClinVar variants found in the HCN1 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-45258986-C-A			Uncertain significance (Jul 23, 2021)
5-45261934-G-A		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Jan 17, 2024)
5-45261935-C-T		Early infantile epileptic encephalopathy with suppression bursts • HCN1-related disorder	Likely benign (Dec 30, 2023)
5-45261940-C-A		Developmental and epileptic encephalopathy, 24	Uncertain significance (-)
5-45261941-G-C			Uncertain significance (Mar 08, 2024)
5-45261953-C-T		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Dec 19, 2023)
5-45261954-G-T		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Aug 15, 2022)
5-45261958-G-A		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Dec 19, 2023)
5-45261958-G-C		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Feb 03, 2023)
5-45261959-G-A		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (May 12, 2023)
5-45261959-G-T		Early infantile epileptic encephalopathy with suppression bursts • Inborn genetic diseases	Conflicting classifications of pathogenicity (Sep 12, 2023)
5-45261960-G-T		Inborn genetic diseases	Uncertain significance (Dec 19, 2022)
5-45261962-C-G		Inborn genetic diseases	Uncertain significance (May 08, 2018)
5-45261974-C-G		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Apr 12, 2023)
5-45261979-G-A		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Oct 17, 2023)
5-45261982-G-A		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Jul 11, 2022)
5-45261988-C-T		Early infantile epileptic encephalopathy with suppression bursts • Inborn genetic diseases	Conflicting classifications of pathogenicity (Aug 14, 2023)
5-45261989-T-C		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Jul 10, 2023)
5-45261990-T-C		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Feb 03, 2022)
5-45261996-A-G		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Apr 03, 2019)
5-45262004-C-T		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Feb 13, 2023)
5-45262013-G-C		Early infantile epileptic encephalopathy with suppression bursts • Inborn genetic diseases	Uncertain significance (Nov 06, 2023)
5-45262013-G-T		Early infantile epileptic encephalopathy with suppression bursts	Conflicting classifications of pathogenicity (Sep 01, 2023)
5-45262022-GA-G		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Aug 21, 2022)
5-45262026-G-T		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Dec 02, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HCN1	protein_coding	protein_coding	ENST00000303230	8	436905

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000108	125743	0	5	125748	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.66	261	489	0.534	0.0000278	5792
Missense in Polyphen		80	216.2	0.37002		2516
Synonymous	-2.32	242	200	1.21	0.0000130	1801
Loss of Function	5.15	2	34.8	0.0575	0.00000196	377

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000443	0.0000439
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Hyperpolarization-activated ion channel exhibiting weak selectivity for potassium over sodium ions (PubMed:28086084). Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). May mediate responses to sour stimuli. {ECO:0000269|PubMed:15351778, ECO:0000269|PubMed:28086084}.
• Disease: DISEASE: Epileptic encephalopathy, early infantile, 24 (EIEE24) [MIM:615871]: A disease characterized by early-onset seizures, intellectual disability of varying degrees, and behavioral disturbances or autistic features in most individuals. {ECO:0000269|PubMed:24747641, ECO:0000269|PubMed:27864847}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Neuronal System;HCN channels;Potassium Channels (Consensus)

Recessive Scores

• pRec: 0.163

Intolerance Scores

• loftool: 0.111
• rvis_EVS: -0.76
• rvis_percentile_EVS: 13.33

Haploinsufficiency Scores

• pHI: 0.581
• hipred: Y
• hipred_score: 0.806
• ghis: 0.658

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.801

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Hcn1
• Phenotype: normal phenotype; 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system 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); craniofacial phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; taste/olfaction phenotype

Gene ontology

• Biological process: regulation of ion transmembrane transport;sodium ion transmembrane transport;regulation of membrane potential;apical protein localization;retinal cone cell development;protein homotetramerization;cellular response to cAMP;potassium ion transmembrane transport
• Cellular component: plasma membrane;integral component of plasma membrane;axon;dendrite;HCN channel complex
• Molecular function: intracellular cAMP-activated cation channel activity;voltage-gated sodium channel activity;voltage-gated potassium channel activity;potassium channel activity;protein binding;voltage-gated cation channel activity;cAMP binding;identical protein binding