ADCY6

adenylate cyclase 6, the group of Adenylate cyclases|MicroRNA protein coding host genes

Basic information

Region (hg38): 12:48766193-48789089

Links

ENSG00000174233 ∙ NCBI:112 ∙ OMIM:600294 ∙ HGNC:237 ∙ Uniprot:O43306 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• lethal congenital contracture syndrome 8 (Moderate), mode of inheritance: AR
• lethal congenital contracture syndrome 8 (Strong), mode of inheritance: AR
• hypomyelination neuropathy-arthrogryposis syndrome (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Lethal congenital contracture syndrome 8	AR	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	Musculoskeletal; Neurologic	24319099

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ADCY6 gene.

• not provided (53 variants)
• Inborn genetic diseases (39 variants)
• Lethal congenital contracture syndrome 8 (4 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ADCY6 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	10	22
missense		1	47	1	2	51
nonsense						0
start loss						0
frameshift						0
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region				3	1	4
non coding				1	15	16
Total	0	1	48	14	27

Highest pathogenic variant AF is 0.00000657

Variants in ADCY6

This is a list of pathogenic ClinVar variants found in the ADCY6 region.

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

Position	Type	Phenotype	Significance	ClinVar
12-48768610-T-A		Inborn genetic diseases	Uncertain significance (Dec 01, 2022)
12-48768619-T-C		Inborn genetic diseases	Uncertain significance (Jun 06, 2023)
12-48768686-C-T		Inborn genetic diseases	Uncertain significance (Jul 12, 2022)
12-48768815-G-A			Benign (May 08, 2021)
12-48768955-C-T			Likely benign (Apr 05, 2018)
12-48768972-G-A		Lethal congenital contracture syndrome 8	Pathogenic (May 01, 2014)
12-48769027-G-A			Benign (Dec 31, 2019)
12-48770699-G-A			Benign (May 19, 2021)
12-48770784-T-A		Inborn genetic diseases	Uncertain significance (Sep 22, 2021)
12-48770829-G-A			Uncertain significance (Sep 01, 2018)
12-48770836-G-A			Likely benign (May 31, 2018)
12-48770844-C-G			Uncertain significance (Mar 10, 2022)
12-48770869-C-T		ADCY6-related disorder	Likely benign (Mar 10, 2023)
12-48770979-C-T			Likely benign (Feb 28, 2018)
12-48771042-T-C			Benign (Nov 10, 2018)
12-48771622-C-T			Benign (May 10, 2021)
12-48771754-C-T		Lethal congenital contracture syndrome 8	Pathogenic (Jan 25, 2021)
12-48771786-T-C		Lethal congenital contracture syndrome 8	Conflicting classifications of pathogenicity (Nov 29, 2023)
12-48771838-A-G		Inborn genetic diseases	Uncertain significance (Oct 30, 2023)
12-48771847-A-T		Inborn genetic diseases	Uncertain significance (Jul 25, 2023)
12-48771864-C-T		Inborn genetic diseases	Uncertain significance (Aug 10, 2021)
12-48771867-C-T		ADCY6-related disorder	Likely benign (Feb 26, 2022)
12-48771895-C-T		Inborn genetic diseases	Uncertain significance (Jul 17, 2023)
12-48771928-G-C			Uncertain significance (Aug 12, 2021)
12-48771968-T-C		ADCY6-related disorder	Likely benign (Oct 29, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ADCY6	protein_coding	protein_coding	ENST00000307885	21	22846

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00583	0.994	125706	0	42	125748	0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.68	567	777	0.729	0.0000528	7575
Missense in Polyphen		189	309.66	0.61035		3059
Synonymous	2.18	267	316	0.844	0.0000208	2424
Loss of Function	4.68	14	49.5	0.283	0.00000237	553

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000418	0.000418
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.000331	0.000323
European (Non-Finnish)	0.000171	0.000158
Middle Eastern	0.00	0.00
South Asian	0.000165	0.000163
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the formation of the signaling molecule cAMP downstream of G protein-coupled receptors (PubMed:17916776, PubMed:17110384). Functions in signaling cascades downstream of beta-adrenergic receptors in the heart and in vascular smooth muscle cells (PubMed:17916776). Functions in signaling cascades downstream of the vasopressin receptor in the kidney and has a role in renal water reabsorption. Functions in signaling cascades downstream of PTH1R and plays a role in regulating renal phosphate excretion. Functions in signaling cascades downstream of the VIP and SCT receptors in pancreas and contributes to the regulation of pancreatic amylase and fluid secretion (By similarity). Signaling mediates cAMP-dependent activation of protein kinase PKA. This promotes increased phosphorylation of various proteins, including AKT. Plays a role in regulating cardiac sarcoplasmic reticulum Ca(2+) uptake and storage, and is required for normal heart ventricular contractibility. May contribute to normal heart function (By similarity). Mediates vasodilatation after activation of beta-adrenergic receptors by isoproterenol (PubMed:17916776). Contributes to bone cell responses to mechanical stimuli (By similarity). {ECO:0000250|UniProtKB:Q01341, ECO:0000250|UniProtKB:Q03343, ECO:0000269|PubMed:17110384, ECO:0000269|PubMed:17916776}.
• Disease: DISEASE: Lethal congenital contracture syndrome 8 (LCCS8) [MIM:616287]: A form of lethal congenital contracture syndrome, an autosomal recessive disorder characterized by degeneration of anterior horn neurons, extreme skeletal muscle atrophy and congenital non-progressive joint contractures. The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth. LCCS8 is an axoglial form of arthrogryposis multiplex congenita, characterized by congenital distal joint contractures, reduced fetal movements, and severe motor paralysis leading to death early in the neonatal period. {ECO:0000269|PubMed:24319099}. 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);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);Vasopressin-regulated water reabsorption - 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);Endocrine and other factor-regulated calcium reabsorption - 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);Pathways in cancer - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Cholinergic synapse - Homo sapiens (human);Taste transduction - Homo sapiens (human);Morphine 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 Adenosine A2A receptor;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;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: 0.219

Intolerance Scores

• loftool: 0.182
• rvis_EVS: -1.19
• rvis_percentile_EVS: 5.9

Haploinsufficiency Scores

• pHI: 0.645
• hipred: Y
• hipred_score: 0.736
• ghis: 0.540

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.501

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Adcy6
• Phenotype: homeostasis/metabolism phenotype; muscle 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); renal/urinary system phenotype

Gene ontology

• Biological process: renal water homeostasis;cAMP biosynthetic process;G protein-coupled receptor signaling pathway;adenylate cyclase-activating G protein-coupled receptor signaling pathway;adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway;dopamine receptor signaling pathway;negative regulation of neuron projection development;negative regulation of urine volume;cellular response to glucagon stimulus;cellular response to prostaglandin E stimulus;cellular response to catecholamine stimulus;regulation of blood vessel diameter;cellular response to vasopressin;cellular response to forskolin
• Cellular component: plasma membrane;integral component of plasma membrane;cilium;membrane;intrinsic component of plasma membrane
• Molecular function: adenylate cyclase activity;protein kinase C binding;protein binding;ATP binding;protein kinase binding;metal ion binding