HCN2

hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2, the group of Cyclic nucleotide gated channels

Basic information

Region (hg38): 19:589881-617159

Previous symbols: [ "BCNG2" ]

Links

ENSG00000099822 ∙ NCBI:610 ∙ OMIM:602781 ∙ HGNC:4846 ∙ Uniprot:Q9UL51 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Febrile seizures, familial, 2	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	20437590; 24324597; 29064616

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HCN2 gene.

• HCN2 related developmental and epileptic encephalopathy (8 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HCN2 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				17	14	31
missense	7		90	11	2	110
nonsense			1			1
start loss						0
frameshift	1		5			6
inframe indel			1	3	1	5
splice donor/acceptor (+/-2bp)				1		1
splice region				2	2	4
non coding					2	2
Total	8	0	97	32	19

Variants in HCN2

This is a list of pathogenic ClinVar variants found in the HCN2 region.

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

Position	Type	Phenotype	Significance	ClinVar
19-589962-G-T		Epilepsy, idiopathic generalized, susceptibility to, 17	Uncertain significance (Nov 03, 2022)
19-589964-G-A		Inborn genetic diseases	Uncertain significance (Dec 22, 2023)
19-589974-C-G		Inborn genetic diseases	Uncertain significance (Nov 17, 2022)
19-589981-G-C		Inborn genetic diseases	Uncertain significance (Aug 20, 2024)
19-589991-G-A		Inborn genetic diseases	Uncertain significance (Jun 07, 2024)
19-590000-G-A		Inborn genetic diseases	Uncertain significance (Nov 12, 2024)
19-590007-GGCC-G		Inborn genetic diseases	Likely benign (May 07, 2024)
19-590007-G-GGCC		Inborn genetic diseases	Likely benign (Sep 19, 2022)
19-590024-C-G		Inborn genetic diseases	Uncertain significance (Mar 19, 2024)
19-590035-C-T		Inborn genetic diseases	Likely benign (Jul 08, 2019)
19-590037-C-A		Inborn genetic diseases	Uncertain significance (May 02, 2024)
19-590052-C-T		Inborn genetic diseases	Benign (May 04, 2022)
19-590074-C-T		Inborn genetic diseases	Likely benign (Oct 23, 2019)
19-590082-G-C			Uncertain significance (Nov 03, 2021)
19-590086-CGG-C			Uncertain significance (Nov 03, 2021)
19-590159-C-T		Inborn genetic diseases	Uncertain significance (Apr 06, 2024)
19-590172-G-A			Benign (Mar 04, 2020)
19-590187-C-G		Inborn genetic diseases	Uncertain significance (Dec 18, 2023)
19-590191-C-T		not specified	Likely benign (Mar 28, 2016)
19-590192-G-C		Inborn genetic diseases	Uncertain significance (Aug 19, 2024)
19-590195-C-T			Uncertain significance (Nov 21, 2023)
19-590198-C-T		Inborn genetic diseases	Uncertain significance (Jul 10, 2024)
19-590204-A-C		Inborn genetic diseases	Uncertain significance (Jul 09, 2021)
19-590219-A-C		Inborn genetic diseases	Uncertain significance (Jul 09, 2021)
19-590222-A-C		Inborn genetic diseases	Uncertain significance (Aug 04, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HCN2	protein_coding	protein_coding	ENST00000251287	8	27267

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.489	0.511	125691	0	7	125698	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.41	222	418	0.531	0.0000285	5672
Missense in Polyphen		32	128.86	0.24833		1170
Synonymous	-5.75	277	179	1.55	0.0000134	1870
Loss of Function	3.53	5	23.5	0.213	0.00000100	296

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000615	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000451	0.0000440
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Hyperpolarization-activated ion channel exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). Can also transport ammonium in the distal nephron. Produces a large instantaneous current. Modulated by intracellular chloride ions and pH; acidic pH shifts the activation to more negative voltages (By similarity). {ECO:0000250, ECO:0000269|PubMed:10228147, ECO:0000269|PubMed:10524219}.
• Pathway: cAMP signaling pathway - Homo sapiens (human);Antiarrhythmic Pathway, Pharmacodynamics;TarBasePathway;Neuronal System;HCN channels;Potassium Channels (Consensus)

Haploinsufficiency Scores

• pHI: 0.161
• hipred: Y
• hipred_score: 0.806
• ghis: 0.650

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.552

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hcn2
• Phenotype: cellular 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; immune system phenotype; hearing/vestibular/ear 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); reproductive system 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); 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); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: cell-cell signaling;regulation of ion transmembrane transport;sodium ion transmembrane transport;regulation of membrane potential;cellular response to cAMP;cellular response to cGMP;potassium ion transmembrane transport;membrane depolarization during cardiac muscle cell action potential;sodium ion import across plasma membrane;potassium ion import across plasma membrane
• Cellular component: plasma membrane;integral component of plasma membrane;voltage-gated potassium channel complex;HCN channel complex
• Molecular function: intracellular cAMP-activated cation channel activity;voltage-gated sodium channel activity;voltage-gated potassium channel activity;protein binding;cAMP binding;identical protein binding