CACNA1I

protein-coding

calcium voltage-gated channel subunit alpha1 I, the group of Calcium voltage-gated channel alpha1 subunits

Gene summary

This gene encodes the pore-forming alpha subunit of a voltage gated calcium channel. The encoded protein is a member of a subfamily of calcium channels referred to as is a low voltage-activated, T-type, calcium channel. The channel encoded by this protein is characterized by a slower activation and inactivation compared to other T-type calcium channels. This protein may be involved in calcium signaling in neurons. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2011]

MANE transcript

NM_021096.4

Inheritance

ClinVar variants

P:7U:548B:108

Top phenotype

Neurodevelopmental disorder with speech impairment and with or without seizures

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr22:39,570,753-39,689,735

External References & Databases

Ensembl (ENSG00000100346)

Transcript & Mutation Effects

hg38 • Region Span ~119.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with speech impairment and with or without seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859313

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Illumina

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with speech impairment and with or without seizuresAD

Manifestation: Musculoskeletal; Neurologic

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: 33704440

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CACNA1I variants in ClinVar

9 Conditions Cataloged

not specifiedTotal: 329

not providedTotal: 245

CACNA1I-related disorderTotal: 101

Neurodevelopmental disorder with speech impairment and with or without seizuresTotal: 73

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

Antenatal intracerebral hemorrhageTotal: 1

VentriculomegalyTotal: 1

Global developmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021096.4. 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			2 clinvar	65 clinvar	11 clinvar	78
missense	3 clinvar	3 clinvar	528 clinvar	29 clinvar	3 clinvar	566
nonsense			4 clinvar			4
start loss						0
frameshift			7 clinvar			7
splice donor/acceptor (+/-2bp)	1 clinvar		7 clinvar			8
Total	4	3	548	94	14	663

Highest pathogenic variant AF is 0.00008974428

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021096.4	RefSeq	NP_066919.2	37	MANE Select
ENST00000402142.4	Ensembl	ENSP00000385019.3	37	MANE Select
NM_001003406.2	RefSeq	NP_001003406.1	36	Standard
ENST00000401624.5	Ensembl	ENSP00000383887.1	36	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cortisol synthesis and secretion - Homo sapiens (human)
Aldosterone synthesis and secretion - Homo sapiens (human)
Cushing,s syndrome - Homo sapiens (human)
Circadian entrainment - Homo sapiens (human)
Calcium signaling pathway - Homo sapiens (human)

Biological Process

signal transduction
neuronal action potential
flagellated sperm motility
sleep
regulation of ion transmembrane transport

Molecular Function

voltage-gated calcium channel activity
protein binding
low voltage-gated calcium channel activity

Cellular Component

plasma membrane
voltage-gated calcium channel complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000402142
Coding exons: 37
Length: 118985
Individuals with no LoFs: 124684
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 124698
p: 0.0000561

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.05	712	1.21e+3	0.591	0.0000759	14276
Missense (PolyPhen)		95	198.11	0.47953		2030
Synonymous	-1.48	577	533	1.08	0.0000365	4536
Loss of Function	7.47	10	83.8	0.119	0.00000425	938

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000061	0.000056	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000063	0.000053	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Voltage-sensitive calcium channels (VSCC) 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 channel gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by nickel and mibefradil. A particularity of this type of channels is an opening at quite negative potentials, and a voltage- dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes. Gates in voltage ranges similar to, but higher than alpha 1G or alpha 1H (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.124

Intolerance Scores

LoFtool: 0.0132
RVIS EVS: -0.83
RVIS percentile EVS: 11.55

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.169

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High