GeneBe

ADCY5

protein-coding

adenylate cyclase 5, the group of Adenylate cyclases

Gene summary

This gene encodes a member of the membrane-bound adenylyl cyclase enzymes. Adenylyl cyclases mediate G protein-coupled receptor signaling through the synthesis of the second messenger cAMP. Activity of the encoded protein is stimulated by the Gs alpha subunit of G protein-coupled receptors and is inhibited by protein kinase A, calcium and Gi alpha subunits. Single nucleotide polymorphisms in this gene may be associated with low birth weight and type 2 diabetes. Alternatively spliced transcript variants that encode different isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

MANE transcript

NM_183357.3

Inheritance

AD, AR, SD

ClinVar variants

P:61U:405B:278

Top phenotype

Dyskinesia with orofacial involvement, autosomal dominant; Dyskinesia with orofacial involvement, autosomal recessive; Neurodevelopmental disorder with hyperkinetic movements and dyskinesia

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr3:123,282,296-123,449,090

External References & Databases

Ensembl (ENSG00000173175)NCBI Gene (111)OMIM (600293)HGNC:236GenCCUniProt (O95622)AlphaFoldClinVar (ADCY5)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~166.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial dyskinesia and facial myokymiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011707

Submitter: Orphanet

neurodevelopmental disorder with hyperkinetic movements and dyskinesiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859211

Submitter: Labcorp Genetics (formerly Invitae)

choreatic diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0001595

Submitter: Orphanet

dyskinesia with orofacial involvementDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0031115

Submitter: ClinGen

*ADCY5* was first reported in relation to dyskinesia with orofacial involvement in 2012 (Chen et al., PMID: 22782511). Dyskinesia with orofacial involvement is a hyperkinetic movement disorder (more prominent in the face and arms than the legs) characterized by infantile to late-adolescent onset of a combination of chorea, athetosis, dystonia, and myoclonus. Variants in *ADCY5* have been reported in individuals with the following disease entities: autosomal dominant dyskinesia with orofacial involvement (OMIM: 606703), autosomal recessive dyskinesia with orofacial involvement (OMIM: 619647), and autosomal recessive neurodevelopmental disorder with hyperkinetic movements and dyskinesia (OMIM: 619651). The phenotype of affected individuals varies greatly, with overlap between the dominant and recessive cases. Although the recessive cases tend to be more severe than the dominant cases, it is postulated that the severity of phenotypes is related to where the variant is located in the gene rather than the inheritance pattern (PMID: 26537056, 31538084). Variants in the C1b domain generally cause mild phenotypes, while those in the C1a and C2a domain lead to more moderate to severe phenotypes (PMID: 26537056, 31538084). Per criteria outlined by the ClinGen Lumping and Splitting guidance, all three disease entities have been lumped into one disease entity of semi-dominant dyskinesia with orofacial involvement. Seventeen variants (missense, splice-site, deletion, frameshift) that have been reported in 17 probands from 10 publications (PMIDs: 22782511, 24700542, 25545163, 27052971, 28971144, 27666935, 30975617, 35002175, 33704598, 34631954) are included in this curation. Variants in this gene segregated with disease in at least 22 family members (PMID: 22782511, 26537056, 30975617). More information is available in the literature, but the maximum score for genetic evidence has been reached (12 points). This gene-disease relationship is also supported by functional alteration studies (PMIDs: 30772269). Two knockout mouse models showed contradictory results, so these models were not scored since we are unclear of the relevance of the models (PMIDs: 12223546, 12665504). In summary, there is definitive evidence to support the relationship between *ADCY5* and semi-dominant dyskinesia with orofacial involvement. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on September 5th, 2024 (SOP Version 10).

neurodevelopmental disorderSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

dyskinesia with orofacial involvement, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0800028

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

familial dyskinesia and facial myokymiaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011707

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Dyskinesia with orofacial involvement, autosomal dominant; Dyskinesia with orofacial involvement, autosomal recessive; Neurodevelopmental disorder with hyperkinetic movements and dyskinesiaAD/AR

Manifestation: Cardiovascular; Endocrine; Neurologic

Intervention: Cardiovascular; Endocrine; Neurologic

Rationale: 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

Refs: 11310626; 22782511; 24700542; 28971144; 30975617; 31731261; 32713175; 33704598; 34631954Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADCY5 variants in ClinVar

17 Conditions Cataloged
not providedTotal: 738
Inborn genetic diseasesTotal: 168
not specifiedTotal: 78
Dyskinesia with orofacial involvement, autosomal dominantTotal: 76
ADCY5-related disorderTotal: 35
Neurodevelopmental disorder with hyperkinetic movements and dyskinesiaTotal: 29
Dyskinesia with orofacial involvement, autosomal recessiveTotal: 28
Dyskinesia with orofacial involvementTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_183357.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
6
clinvar
187
clinvar
12
clinvar
 205
missense
7
clinvar
19
clinvar
392
clinvar
72
clinvar
7
clinvar
 497
nonsense
4
clinvar
4
clinvar
1
clinvar
 9
start loss
0
frameshift
9
clinvar
9
clinvar
3
clinvar
 21
splice donor/acceptor (+/-2bp)
4
clinvar
5
clinvar
3
clinvar
 12
Total243740525919744

Highest pathogenic variant AF is 0.000030933563

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_183357.3RefSeqNP_899200.121MANE Select
ENST00000462833.6EnsemblENSP00000419361.121MANE Select
NM_001199642.1RefSeqNP_001186571.121Standard
NM_001378259.1RefSeqNP_001365188.122Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
adcy5Danio rerio

Structure: protein kinase regulator activity

Quality: disrupted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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)

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

Molecular Function

  • adenylate cyclase activity
  • ATP binding
  • adenylate cyclase binding
  • metal ion binding
  • protein heterodimerization activity

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • cilium
  • integral component of membrane
  • intermediate filament cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000462833
Coding exons
21
Length
167463
Individuals with no LoFs
125734
Homozygous LoFs
0
Heterozygous LoFs
14
Defined
125748
p
0.0000557
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.404917540.6510.00005028188
Missense (PolyPhen)103269.40.382342746
Synonymous0.09263413430.9940.00002612571
Loss of Function5.77751.80.1350.00000266576

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish0.000210.00020rare
East Asian0.000110.00011rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000350.000035rare
South Asian0.0000980.000098rare
Other00.0absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.233

Intolerance Scores

LoFtool
0.200
RVIS EVS
-2.39
RVIS percentile EVS
1.1

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.945

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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