CACNA1F

protein-coding

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

Gene summary

This gene encodes a multipass transmembrane protein that functions as an alpha-1 subunit of the voltage-dependent calcium channel, which mediates the influx of calcium ions into the cell. The encoded protein forms a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Mutations in this gene can cause X-linked eye disorders, including congenital stationary night blindness type 2A, cone-rod dystropy, and Aland Island eye disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [provided by RefSeq, Aug 2013]

Previous symbols:

CSNB2
AIED

MANE transcript

NM_001256789.3

Inheritance

XL, AD

ClinVar variants

P:253U:773B:374

Top phenotype

Aland Island eye disease; Cone-rod dystrophy, X-linked, 3; Night blindness, congenital stationary, X-linked, type 2A

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chrX:49,205,063-49,233,371

External References & Databases

Ensembl (ENSG00000102001)

Transcript & Mutation Effects

hg38 • Region Span ~28.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

CACNA1F-related retinopathyDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0700243

Submitter: ClinGen

*CACNA1F* was first reported in relation to cases of X-linked inheritance of incomplete congenital stationary night blindness in 1998 by two groups (Bech-Hansen et al., PMID: 9662400 and Strom et al., PMID: 9662399). *CACNA1F* has been noted to be associated with the following disease entities as found in OMIM: Aland Island eye disease (OMIM:300600); X-linked cone-rod dystrophy 3 (OMIM:300476); and incomplete, X-linked congenital stationary night blindness (OMIM:30071). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in the molecular mechanism or inheritance pattern of these diseases. Therefore, these three disease entities have been lumped into a single disease entity, named CACNA1F-related retinopathy for the gene curation of *CACNA1F*. 17 suspected pathogenic variants (six missense, one in-frame indel, five nonsense, two frameshift, and three splicing) that have been reported in 17 probands across seven publications (PMIDs: 16505158, 11281458, 26992781, 22194652, 12111638, 23714322, and 9662400) are included in this curation. Each proband was a hemizygous male. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be monoallelic loss of function. This gene-disease association is also supported by experimental evidence that *CACNA1F* exhibits its highest expression levels in retina tissue, specifically the outer plexiform layer of retina cells (PMIDs: 9662400, 9662399, 11527958). *Cacna1f* knockout mice exhibit absence of scotopic b-wave and normal a-wave in ERG recordings; significantly reduced calcium signaling; reduced Cacna1f, M-opsin and S-opsin expression in the retina and reduced thickness of the outer plexiform layer of the retina (PMIDs: 16155113, 30445045). In summary, *CACNA1F* is definitively associated with X-linked inheritance of CACNA1F-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Retina GCEP on January 5th, 2023 (SOP Version 9).

Aland island eye diseaseSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010371

Submitter: Labcorp Genetics (formerly Invitae)

X-linked cone-rod dystrophy 3STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010335

Submitter: Labcorp Genetics (formerly Invitae)

cone-rod dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: Orphanet

Aland island eye diseaseSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010371

Submitter: Orphanet

congenital stationary night blindness 2ASTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010241

Submitter: Labcorp Genetics (formerly Invitae)

Aland island eye diseaseDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010371

Submitter: G2P

Clinical Genomic Database (CGD)

Aland Island eye disease; Cone-rod dystrophy, X-linked, 3; Night blindness, congenital stationary, X-linked, type 2AXL

Manifestation: Ophthalmologic

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: 14230113; 14213931; 9662400; 9662399; 11381068; 12111638; 12807962; 16505158; 17525176; 20001510; 20301423; 22194652; 22744390

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CACNA1F variants in ClinVar

23 Conditions Cataloged

not providedTotal: 1404

CACNA1F-related disorderTotal: 246

not specifiedTotal: 240

Inborn genetic diseasesTotal: 135

Congenital stationary night blindness 2ATotal: 67

X-linked cone-rod dystrophy 3Total: 45

Aland island eye diseaseTotal: 39

Retinal dystrophyTotal: 28

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001256789.3. 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		1 clinvar	15 clinvar	288 clinvar	2 clinvar	306
missense	5 clinvar	30 clinvar	736 clinvar	78 clinvar	5 clinvar	854
nonsense	49 clinvar	18 clinvar	3 clinvar			70
start loss			1 clinvar			1
frameshift	45 clinvar	40 clinvar	3 clinvar			88
splice donor/acceptor (+/-2bp)	16 clinvar	49 clinvar	15 clinvar	1 clinvar		81
Total	115	138	773	367	7	1400

Highest pathogenic variant AF is 0.000018252505

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001256789.3	RefSeq	NP_001243718.1	48	MANE Select
ENST00000323022.10	Ensembl	ENSP00000321618.6	48	MANE Select
NM_001256790.3	RefSeq	NP_001243719.1	48	Standard
NM_005183.4	RefSeq	NP_005174.2	48	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cacna1fa	Danio rerio	Structure: retinal cone cell Quality: quality abnormal

Gene / Model

Organism

Observed Phenotype

cacna1fa

Danio rerio

Structure: retinal cone cell

Quality: quality

abnormal

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)
Oxytocin signaling pathway - Homo sapiens (human)
Retrograde endocannabinoid signaling - Homo sapiens (human)
GABAergic synapse - Homo sapiens (human)

Biological Process

calcium ion transport
visual perception
regulation of ion transmembrane transport
T cell homeostasis
regulation of T cell receptor signaling pathway

Molecular Function

voltage-gated calcium channel activity
high voltage-gated calcium channel activity
metal ion binding

Cellular Component

photoreceptor outer segment
plasma membrane
voltage-gated calcium channel complex
integral component of membrane
perikaryon

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000376265
Coding exons: 48
Length: 28311
Individuals with no LoFs: 125712
Homozygous LoFs: 13
Heterozygous LoFs: 22
Defined: 125747
p: 0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.60	632	845	0.748	0.0000704	12869
Missense (PolyPhen)		128	198.73	0.64408		3093
Synonymous	1.60	301	338	0.889	0.0000285	3980
Loss of Function	5.40	23	72.7	0.316	0.00000574	1114

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00044	0.00031	rare
Latino/Admixed American	0.00022	0.00017	rare
Ashkenazi Jewish	0.00014	0.000099	rare
East Asian	0.00044	0.00033	rare
Finnish	0.000064	0.000046	rare
European (Non-Finnish)	0.00013	0.000088	rare
South Asian	0.00027	0.00016	rare
Other	0.00022	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Isoform 1: 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. The isoform alpha-1F gives rise to L-type calcium currents. Long- lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, and by benzothiazepines. Activates at more negative voltages and does not undergo calcium-dependent inactivation (CDI), due to incoming calcium ions, during depolarization. {ECO:0000269|PubMed:27226626}.; FUNCTION: Isoform 6: Voltage-dependent L-type calcium channel activates at more hyperpolarized voltages and exibits a robust calcium-dependent inactivation (CDI), due to incoming calcium ions, during depolarizations. {ECO:0000269|PubMed:27226626}.;
Disease: DISEASE: Night blindness, congenital stationary, 2A (CSNB2A) [MIM:300071]: A non-progressive retinal disorder characterized by impaired night vision, often associated with nystagmus and myopia. {ECO:0000269|PubMed:11281458, ECO:0000269|PubMed:12111638, ECO:0000269|PubMed:12187427, ECO:0000269|PubMed:15897456, ECO:0000269|PubMed:22194652, ECO:0000269|PubMed:9662399, ECO:0000269|PubMed:9662400}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cone-rod dystrophy, X-linked 3 (CORDX3) [MIM:300476]: An inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. {ECO:0000269|PubMed:16505158}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Aaland island eye disease (AIED) [MIM:300600]: A retinal disease characterized by a combination of fundus hypopigmentation, decreased visual acuity due to foveal hypoplasia, nystagmus, astigmatism, protan color vision defect, myopia, and defective dark adaptation. Except for progression of axial myopia, the disease can be considered to be a stationary condition. Electroretinography reveals abnormalities in both photopic and scotopic functions. {ECO:0000269|PubMed:17525176, ECO:0000269|PubMed:22194652}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.198

Intolerance Scores

LoFtool: 0.0573
RVIS EVS: -0.83
RVIS percentile EVS: 11.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.690

Gene Damage Prediction

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