ADCY10

protein-coding

adenylate cyclase 10, the group of Adenylate cyclases

Gene summary

The protein encoded by this gene belongs to a distinct class of adenylyl cyclases that is soluble and insensitive to G protein or forskolin regulation. Activity of this protein is regulated by bicarbonate. Variation at this gene has been observed in patients with absorptive hypercalciuria. Alternatively spliced transcript variants encoding different isoforms have been observed. There is a pseudogene of this gene on chromosome 6. [provided by RefSeq, Jul 2014]

MANE transcript

NM_018417.6

Inheritance

ClinVar variants

P:37U:321B:149

Top phenotype

Hypercalciuria, absorptive, 2

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr1:167,809,386-167,914,215

External References & Databases

Ensembl (ENSG00000143199)

Transcript & Mutation Effects

hg38 • Region Span ~104.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypercalciuria, absorptive, 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007748

Submitter: Ambry Genetics

hypercalciuria, absorptive, 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007748

Submitter: PanelApp Australia

idiopathic inherited hypercalciuriaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016352

Submitter: Orphanet

hypercalciuria, absorptive, 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007748

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Hypercalciuria, absorptive, 2AD

Manifestation: Renal

Intervention: General

Rationale: 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

Refs: 11932268

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADCY10 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 428

not specifiedTotal: 228

ADCY10-related disorderTotal: 65

Familial idiopathic hypercalciuriaTotal: 52

Abnormal sperm morphologyTotal: 1

Male infertilityTotal: 1

Reduced sperm motilityTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018417.6. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	95 clinvar	4 clinvar	104
missense			309 clinvar	46 clinvar	4 clinvar	359
nonsense	9 clinvar	6 clinvar	4 clinvar			19
start loss						0
frameshift	8 clinvar	5 clinvar				13
splice donor/acceptor (+/-2bp)		9 clinvar	3 clinvar			12
Total	17	20	321	141	8	507

Highest pathogenic variant AF is 0.00030420182

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018417.6	RefSeq	NP_060887.2	32	MANE Select
ENST00000367851.9	Ensembl	ENSP00000356825.4	32	MANE Select
NM_001167749.3	RefSeq	NP_001161221.1	28	Standard
NM_001297772.2	RefSeq	NP_001284701.1	29	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Circadian entrainment - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)
cAMP signaling pathway - Homo sapiens (human)
Apelin signaling pathway - Homo sapiens (human)
Purine metabolism - Homo sapiens (human)

Biological Process

epithelial cilium movement
cAMP biosynthetic process
spermatogenesis
intracellular signal transduction
positive regulation of apoptotic process

Molecular Function

magnesium ion binding
adenylate cyclase activity
ATP binding
manganese ion binding
ATPase binding

Cellular Component

nucleus
cytoplasm
mitochondrion
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367851
Coding exons: 32
Length: 104829
Individuals with no LoFs: 125442
Homozygous LoFs: 0
Heterozygous LoFs: 306
Defined: 125748
p: 0.00122

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.455	788	825	0.955	0.0000436	10780
Missense (PolyPhen)		217	245.12	0.88528		3334
Synonymous	-0.381	309	301	1.03	0.0000168	2853
Loss of Function	1.29	69	81.5	0.846	0.00000455	1003

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00055	0.00055	rare
Latino/Admixed American	0.00075	0.00075	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.0018	0.0017	notable
Finnish	0.0018	0.0018	notable
European (Non-Finnish)	0.0014	0.0014	notable
South Asian	0.0011	0.0011	notable
Other	0.0015	0.0015	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the formation of the signaling molecule cAMP (PubMed:12609998, PubMed:15659711, PubMed:24616449, PubMed:25040695, PubMed:24567411). May function as sensor that mediates responses to changes in cellular bicarbonate and CO(2) levels (PubMed:15659711, PubMed:17591988). Has a critical role in mammalian spermatogenesis by producing the cAMP which regulates cAMP-responsive nuclear factors indispensable for sperm maturation in the epididymis. Induces capacitation, the maturational process that sperm undergo prior to fertilization (By similarity). Involved in ciliary beat regulation (PubMed:17591988). {ECO:0000250|UniProtKB:Q8C0T9, ECO:0000269|PubMed:15659711, ECO:0000269|PubMed:17591988, ECO:0000269|PubMed:24567411, ECO:0000269|PubMed:24616449, ECO:0000269|PubMed:25040695}.;
Disease: DISEASE: Hypercalciuria absorptive 2 (HCA2) [MIM:143870]: A common type of hypercalciuria, a condition characterized by excessive urinary calcium excretion. Absorptive hypercalciuria is due to gastrointestinal hyperabsorption of calcium and is a frequent cause of calcium oxalate nephrolithiasis. {ECO:0000269|PubMed:11932268}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0626

Intolerance Scores

LoFtool: 0.982
RVIS EVS: 0.64
RVIS percentile EVS: 83.79

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.152

Gene Damage Prediction

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