ADCY2

Chr 5

adenylate cyclase 2

Also known as: AC2, HBAC2

NCBI Gene: 108 ENSG00000078295 UniProt: Q08462

The protein catalyzes the formation of cyclic adenosine monophosphate (cAMP), a critical second messenger that mediates G-protein signaling cascades and regulates gene expression patterns. Mutations cause autosomal recessive developmental and epileptic encephalopathy with early-onset seizures and severe developmental delay. This gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely incompatible with normal development.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the family of adenylate cyclases, which are membrane-associated enzymes that catalyze the formation of the secondary messenger cyclic adenosine monophosphate (cAMP). This enzyme is insensitive to Ca(2+)/calmodulin, and is stimulated by the G protein beta and gamma subunit complex. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.26

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.26LOEUF

pLI 0.999

Z-score 5.89

OE 0.14 (0.08–0.26)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

4.25Z-score

OE missense 0.53 (0.48–0.58)

343 obs / 647.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.14 (0.08–0.26)

0≤0.351.4

Missense OE?0.53 (0.48–0.58)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 8 / 55.2Missense obs/exp: 343 / 647.0Syn Z: 0.87

Background carrier burden — how many people carry a rare variant somewhere in ADCY2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 75

973 rare PASS variants

Rare truncating (LoF)

1 in 590

81 rare PASS variants

Rare synonymous (reference)

1 in 62

545 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ADCY2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 100	1 in 880
South Asian	~43k	1 in 89	1 in 2,100
Remaining (unassigned)	~30k	1 in 67	1 in 1,200
European (Finnish)	~27k	1 in 180	1 in 500
Admixed American	~22k	1 in 82	1 in 820
African / African American	~21k	1 in 83	1 in 380
East Asian	~20k	1 in 80	1 in 2,000
Ashkenazi Jewish	~13k	1 in 240	≈ 1 in 4,300
Middle Eastern	~2,884	1 in 64	1 in 440

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 22 of 25 coding exons well covered in gnomAD exomes; exons 11, 12, 13 marginal. Genomes: all 25.? see exons ↓