ADCY5

adenylate cyclase 5, the group of Adenylate cyclases

Basic information

Region (hg38): 3:123282295-123449090

Links

ENSG00000173175 ∙ NCBI:111 ∙ OMIM:600293 ∙ HGNC:236 ∙ Uniprot:O95622 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• familial dyskinesia and facial myokymia (Moderate), mode of inheritance: AD
• dyskinesia with orofacial involvement, autosomal dominant (Strong), mode of inheritance: AD
• choreatic disease (Supportive), mode of inheritance: AD
• familial dyskinesia and facial myokymia (Supportive), mode of inheritance: AD
• neurodevelopmental disorder with hyperkinetic movements and dyskinesia (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Dyskinesia with orofacial involvement, autosomal dominant; Dyskinesia with orofacial involvement, autosomal recessive; Neurodevelopmental disorder with hyperkinetic movements and dyskinesia	AD/AR	Cardiovascular; Endocrine; Neurologic	In addition to neurologic manifestations, individuals have been described with dilated cardiomyopathy and congestive heart failure, and awareness may allow surveillance (eg, with echocardiography), and early management; Caffeine has been described as beneficial related to the dyskinetic episodes in an individual with a dominant form of the condition; Hypothyroidism has been described in Dyskinesia with orofacial involvement, autosomal recessive, and awareness may allow early identification and medical management	Cardiovascular; Endocrine; Neurologic	11310626; 22782511; 24700542; 28971144; 30975617; 31731261; 32713175; 33704598; 34631954

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ADCY5 gene.

• not provided (571 variants)
• Dyskinesia with orofacial involvement, autosomal dominant (71 variants)
• Inborn genetic diseases (52 variants)
• Dyskinesia with orofacial involvement, autosomal recessive (28 variants)
• Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (26 variants)
• not specified (13 variants)
• Dyskinesia with orofacial involvement, autosomal dominant;Dyskinesia with orofacial involvement, autosomal recessive;Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (5 variants)
• ADCY5-related disorder (1 variants)
• Distal myopathy with posterior leg and anterior hand involvement (1 variants)
• Neurodevelopmental delay (1 variants)
• See cases (1 variants)
• ADCY5-related condition (1 variants)
• Dyskinesia with orofacial involvement, autosomal recessive;Neurodevelopmental disorder with hyperkinetic movements and dyskinesia;Dyskinesia with orofacial involvement, autosomal dominant (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ADCY5 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	109	20	135
missense	4	15	192	27	12	250
nonsense	4	3				7
start loss						0
frameshift	6	3				9
inframe indel			7			7
splice donor/acceptor (+/-2bp)	1	4				5
splice region			9	16	2	27
non coding			3	80	83	166
Total	15	25	208	216	115

Highest pathogenic variant AF is 0.00000659

Variants in ADCY5

This is a list of pathogenic ClinVar variants found in the ADCY5 region.

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

Position	Type	Phenotype	Significance	ClinVar
3-123284451-C-A			Likely benign (Jul 05, 2018)
3-123284604-GCTGCTAA-G			Uncertain significance (Jan 01, 2024)
3-123284607-GCTAA-G			Uncertain significance (Aug 23, 2022)
3-123284617-C-T		Dyskinesia with orofacial involvement, autosomal recessive • Neurodevelopmental disorder with hyperkinetic movements and dyskinesia • Dyskinesia with orofacial involvement, autosomal dominant	Benign/Likely benign (Jan 18, 2024)
3-123284618-G-A		ADCY5-related disorder	Likely benign (Jan 29, 2024)
3-123284630-T-C		Inborn genetic diseases	Uncertain significance (Mar 01, 2024)
3-123284639-T-C			Uncertain significance (Sep 29, 2021)
3-123284645-A-G			Uncertain significance (Sep 13, 2022)
3-123284646-T-G			Uncertain significance (May 05, 2022)
3-123284652-C-T			Uncertain significance (Jan 14, 2023)
3-123284653-G-T			Likely benign (Jun 27, 2022)
3-123284658-T-C			Uncertain significance (Jul 17, 2021)
3-123284660-CCCTTGA-C			Uncertain significance (Dec 09, 2022)
3-123284677-G-A		Inborn genetic diseases	Likely benign (Dec 12, 2023)
3-123284682-G-A		Neurodevelopmental disorder with hyperkinetic movements and dyskinesia	Pathogenic (Dec 08, 2021)
3-123284684-C-T			Uncertain significance (Dec 30, 2021)
3-123284698-C-T		Dyskinesia with orofacial involvement, autosomal recessive • Neurodevelopmental disorder with hyperkinetic movements and dyskinesia • Dyskinesia with orofacial involvement, autosomal dominant	Benign/Likely benign (Sep 10, 2023)
3-123284699-G-A		Inborn genetic diseases	Uncertain significance (Dec 22, 2023)
3-123284710-C-T			Conflicting classifications of pathogenicity (Sep 30, 2023)
3-123284715-C-T			Uncertain significance (Jun 27, 2023)
3-123284725-G-A			Uncertain significance (Sep 01, 2020)
3-123284739-G-A			Uncertain significance (Nov 01, 2020)
3-123284745-G-T			Likely benign (Aug 28, 2021)
3-123284748-CAGG-C			Likely benign (Aug 09, 2022)
3-123284754-G-A			Likely benign (Sep 30, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ADCY5	protein_coding	protein_coding	ENST00000462833	21	167463

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.000719	125734	0	14	125748	0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.40	491	754	0.651	0.0000502	8188
Missense in Polyphen		103	269.4	0.38234		2746
Synonymous	0.0926	341	343	0.994	0.0000261	2571
Loss of Function	5.77	7	51.8	0.135	0.00000266	576

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000579	0.0000579
Ashkenazi Jewish	0.000206	0.000198
East Asian	0.000110	0.000109
Finnish	0.0000464	0.0000462
European (Non-Finnish)	0.0000352	0.0000352
Middle Eastern	0.000110	0.000109
South Asian	0.0000981	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling (PubMed:15385642, PubMed:26206488, PubMed:24700542). Mediates signaling downstream of ADRB1 (PubMed:24700542). Regulates the increase of free cytosolic Ca(2+) in response to increased blood glucose levels and contributes to the regulation of Ca(2+)-dependent insulin secretion (PubMed:24740569). {ECO:0000269|PubMed:15385642, ECO:0000269|PubMed:24700542, ECO:0000269|PubMed:24740569, ECO:0000269|PubMed:26206488}.
• Disease: DISEASE: Dyskinesia, familial, with facial myokymia (FDFM) [MIM:606703]: A disorder characterized by predominantly perioral and periorbital myokymia, and face, neck and upper limb dystonic/choreic movements. Initially paroxysmal and worsened by stress, the dyskinetic episodes become nearly constant by the end of the third decade of life, but in some individuals, they may diminish in frequency and severity at older ages. {ECO:0000269|PubMed:22782511, ECO:0000269|PubMed:24700542}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Inflammatory mediator regulation of TRP channels - Homo sapiens (human);Platelet activation - Homo sapiens (human);Cortisol synthesis and secretion - Homo sapiens (human);Relaxin signaling pathway - Homo sapiens (human);Aldosterone synthesis and secretion - Homo sapiens (human);Regulation of lipolysis in adipocytes - Homo sapiens (human);Oxytocin signaling pathway - Homo sapiens (human);Retrograde endocannabinoid signaling - Homo sapiens (human);GABAergic synapse - Homo sapiens (human);Serotonergic synapse - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Glutamatergic synapse - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Oocyte meiosis - Homo sapiens (human);Dilated cardiomyopathy (DCM) - Homo sapiens (human);Thyroid hormone synthesis - Homo sapiens (human);Longevity regulating pathway - multiple species - Homo sapiens (human);GnRH signaling pathway - Homo sapiens (human);Bile secretion - Homo sapiens (human);Gap junction - Homo sapiens (human);Gastric acid secretion - Homo sapiens (human);Chemokine signaling pathway - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Longevity regulating pathway - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Estrogen signaling pathway - Homo sapiens (human);Vascular smooth muscle contraction - Homo sapiens (human);Renin secretion - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Salivary secretion - Homo sapiens (human);Pancreatic secretion - Homo sapiens (human);Phospholipase D signaling pathway - Homo sapiens (human);Purine metabolism - Homo sapiens (human);Amphetamine addiction - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Parkinson,s disease - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Cholinergic synapse - Homo sapiens (human);Morphine addiction - Homo sapiens (human);Alcoholism - Homo sapiens (human);Cocaine addiction - Homo sapiens (human);Ovarian steroidogenesis - Homo sapiens (human);Insulin secretion - Homo sapiens (human);Melanogenesis - Homo sapiens (human);Progesterone-mediated oocyte maturation - Homo sapiens (human);Proton Pump Inhibitor Pathway, Pharmacodynamics;Beta-agonist/Beta-blocker Pathway, Pharmacodynamics;Myometrial Relaxation and Contraction Pathways;G Protein Signaling Pathways;Chemokine signaling pathway;Phosphodiesterases in neuronal function;Calcium Regulation in the Cardiac Cell;Signaling by GPCR;Signal Transduction;Glucagon signaling in metabolic regulation;GPCR Dopamine D1like receptor;GPCR Adenosine A2A receptor;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Purine metabolism;Metabolism;PKA activation;PKA-mediated phosphorylation of CREB;G alpha (s) signalling events;Calmodulin induced events;CaM pathway;Adrenaline,noradrenaline inhibits insulin secretion;Transport of small molecules;Glucagon-like Peptide-1 (GLP1) regulates insulin secretion;Regulation of insulin secretion;Neuronal System;GPCR signaling-G alpha s Epac and ERK;Hedgehog ,off, state;GPCR signaling-G alpha s PKA and ERK;Signaling by Hedgehog;Purine nucleotides nucleosides metabolism;Adenylate cyclase inhibitory pathway;Inhibition of adenylate cyclase pathway;Activation of GABAB receptors;DAG and IP3 signaling;GABA B receptor activation;Ca-dependent events;PLC beta mediated events;GABA receptor activation;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;Adenylate cyclase activating pathway;G-protein mediated events;Opioid Signalling;G alpha (i) signalling events;G alpha (z) signalling events;PKA activation in glucagon signalling;GPCR signaling-G alpha i;Vasopressin regulates renal water homeostasis via Aquaporins;Aquaporin-mediated transport;Integration of energy metabolism;GPCR downstream signalling;Intracellular signaling by second messengers;LPA4-mediated signaling events;LPA receptor mediated events;Endothelins (Consensus)

Recessive Scores

• pRec: 0.233

Intolerance Scores

• loftool: 0.200
• rvis_EVS: -2.39
• rvis_percentile_EVS: 1.1

Haploinsufficiency Scores

• pHI: 0.417
• hipred: Y
• hipred_score: 0.736
• ghis: 0.624

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.945

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Adcy5
• Phenotype: homeostasis/metabolism phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: adcy5
• Affected structure: protein kinase regulator activity
• Phenotype tag: abnormal
• Phenotype quality: disrupted

Gene ontology

• Biological process: adenosine receptor signaling pathway;renal water homeostasis;cAMP biosynthetic process;G protein-coupled receptor signaling pathway;adenylate cyclase-activating G protein-coupled receptor signaling pathway;adenylate cyclase-activating dopamine receptor signaling pathway;adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway;adenylate cyclase-inhibiting dopamine receptor signaling pathway;positive regulation of cytosolic calcium ion concentration;locomotory behavior;neuromuscular process controlling balance;regulation of insulin secretion involved in cellular response to glucose stimulus;cellular response to glucagon stimulus;cellular response to forskolin
• Cellular component: plasma membrane;integral component of plasma membrane;cilium;integral component of membrane;intermediate filament cytoskeleton
• Molecular function: adenylate cyclase activity;ATP binding;adenylate cyclase binding;metal ion binding;protein heterodimerization activity;scaffold protein binding