CACNA1E

Chr 1AD

calcium voltage-gated channel subunit alpha1 E

Also known as: BII, CACH6, CACNL1A6, Cav2.3, DEE69, EIEE69, gm139

NCBI Gene: 777 ENSG00000198216 UniProt: Q15878 OMIM: 601013

The protein forms the alpha-1E subunit of R-type voltage-dependent calcium channels that mediate calcium entry into excitable cells and modulate neuronal firing patterns important for information processing. Mutations cause developmental and epileptic encephalopathy 69 with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants, and mutations can cause disease through multiple mechanisms depending on the specific variant type.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Voltage-dependent calcium channels are multisubunit complexes consisting of alpha-1, alpha-2, beta, and delta subunits in a 1:1:1:1 ratio. These channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. This gene encodes the alpha-1E subunit of the R-type calcium channels, which belong to the 'high-voltage activated' group that maybe involved in the modulation of firing patterns of neurons important for information processing. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 69MIM #618285

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · genetic developmental and epileptic encephalopathy · AD · ClinGen 2023
Definitive · developmental and epileptic encephalopathy, 69 · AD · Ambry Genetics
Moderate · neurodevelopmental disorder · AD · Ambry Genetics

Interpreting a novel variant

Gain of function is the established mechanism, so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.12

LOEUF· LoF intol.

GOF

Mechanism· annotated

📖

GeneReview available — CACNA1E

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.12LOEUF

pLI 1.000

Z-score 9.29

OE 0.07 (0.04–0.12)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.81Z-score

OE missense 0.56 (0.52–0.59)

750 obs / 1351.3 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.07 (0.04–0.12)

0≤0.351.4

Missense OE?0.56 (0.52–0.59)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 8 / 115.9Missense obs/exp: 750 / 1351.3Syn Z: -0.21

Background carrier burden — how many people carry a rare variant somewhere in CACNA1E?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 26

2,118 rare PASS variants

Rare truncating (LoF)

1 in 430

92 rare PASS variants

Rare synonymous (reference)

1 in 34

1,234 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CACNA1E. 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 30	1 in 2,000
South Asian	~43k	1 in 26	1 in 1,300
Remaining (unassigned)	~30k	1 in 23	1 in 480
European (Finnish)	~27k	1 in 82	1 in 1,300
Admixed American	~22k	1 in 25	1 in 870
African / African American	~21k	1 in 30	1 in 480
East Asian	~20k	1 in 29	1 in 370
Ashkenazi Jewish	~13k	1 in 92	1 in 620
Middle Eastern	~2,884	1 in 36	1 in 460

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 30 of 48 coding exons well covered in gnomAD exomes; exons 2, 4, 8, 9, 10 and 13 more marginal. Genomes: 47 of 48 (exon 40 below).? see exons ↓