ADCY1

protein-coding

adenylate cyclase 1, the group of Adenylate cyclases

Gene summary

This gene encodes a member of the of adenylate cyclase gene family that is primarily expressed in the brain. This protein is regulated by calcium/calmodulin concentration and may be involved in brain development. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

Previous symbols:

DFNB44

MANE transcript

NM_021116.4

Inheritance

ClinVar variants

P:1U:165B:113

Top phenotype

Deafness, autosomal dominant 44

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr7:45,574,140-45,723,116

External References & Databases

Ensembl (ENSG00000164742)

Transcript & Mutation Effects

hg38 • Region Span ~149.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss, autosomal recessiveLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 44LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012421

Submitter: PanelApp Australia

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

*ADCY1* was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2014 (Santos-Cortez et al., PMID: 24482543). A nonsense variant that has been reported in a proband in 1 publication is included in this curation (PMID: 24482543). The variant segregated with disease in 7 additional family members. The mechanism of pathogenicity is unknown. This gene-disease relationship is also supported by an expression study and a zebrafish model (PMID: 24482543). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on 05/10/2017 as per SOP v4. It was reevaluated on 10/31/2024 using SOP v11. As a result of this reevaluation, this record underwent an update in scoring to be consistent with SOP v11. There has been no new evidence published since the last curation.

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 44LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012421

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 44AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 15583425; 24482543

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADCY1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 296

Inborn genetic diseasesTotal: 75

not specifiedTotal: 42

ADCY1-related disorderTotal: 33

Autosomal recessive nonsyndromic hearing loss 44Total: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021116.4. 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			3 clinvar	102 clinvar	2 clinvar	107
missense			159 clinvar	7 clinvar	2 clinvar	168
nonsense		1 clinvar	1 clinvar			2
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	1	165	109	4	279

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021116.4	RefSeq	NP_066939.1	20	MANE Select
ENST00000297323.12	Ensembl	ENSP00000297323.7	20	MANE Select
NM_001281768.2	RefSeq	NP_001268697.1	8	Standard
ENST00000432715.5	Ensembl	ENSP00000392721.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
adcy1b	Danio rerio	Structure: auditory receptor cell Quality: decreased functionality abnormal

Gene / Model

Organism

Observed Phenotype

adcy1b

Danio rerio

Structure: auditory receptor cell

Quality: decreased functionality

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

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

Molecular Function

adenylate cyclase activity
calmodulin binding
ATP binding
calcium- and calmodulin-responsive adenylate cyclase activity
metal ion binding

Cellular Component

nucleus
cytoplasm
plasma membrane
integral component of plasma membrane
membrane raft

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000297323
Coding exons: 20
Length: 148977
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125748
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.38	347	665	0.522	0.0000408	7205
Missense (PolyPhen)		87	263.14	0.33062		2645
Synonymous	0.195	287	291	0.985	0.0000192	2381
Loss of Function	5.51	7	48.4	0.145	0.00000259	526

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000089	0.000087	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling. Mediates responses to increased cellular Ca(2+)/calmodulin levels (By similarity). May be involved in regulatory processes in the central nervous system. May play a role in memory and learning. Plays a role in the regulation of the circadian rhythm of daytime contrast sensitivity probably by modulating the rhythmic synthesis of cyclic AMP in the retina (By similarity). {ECO:0000250|UniProtKB:O88444, ECO:0000250|UniProtKB:P19754}.;
Disease: DISEASE: Deafness, autosomal recessive, 44 (DFNB44) [MIM:610154]: A form of non-syndromic deafness characterized by prelingual profound hearing loss affecting all frequencies. {ECO:0000269|PubMed:24482543}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.181

Intolerance Scores

LoFtool: 0.134
RVIS EVS: -1.39
RVIS percentile EVS: 4.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.399

Gene Damage Prediction

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