CNGA1
protein-codingcyclic nucleotide gated channel subunit alpha 1, the group of Cyclic nucleotide gated channels
Gene summary
The protein encoded by this gene is involved in phototransduction. Along with another protein, the encoded protein forms a cGMP-gated cation channel in the plasma membrane, allowing depolarization of rod photoreceptors. This represents the last step in the phototransduction pathway. Defects in this gene are a cause of retinitis pigmentosa autosomal recessive (ARRP) disease. Multiple transcript variants have been found for this gene. [provided by RefSeq, Oct 2019]
- CNCG1
- CNCG
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~80.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013405
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013405
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0800405
Submitter: ClinGen
The *CNGA1* gene was first reported in relation to autosomal recessive retinitis pigmentosa (arRP) in 1995 (Dryja et al., PMID: 7479749). *CNGA1*-related arRP is reported to exhibit classic RP symptoms including night blindness, progressive visual loss, attenuated blood vessels, pale optic discs, bone spicule pigmentation, thinning of retinal membranes, progressive loss of visual field, reduced scotopic and photopic electroretinography recordings and blindness. Because of the broad spectrum of potential phenotypes, these cases with causal variants in *CNGA1* have been curated under the inclusive disease name *CNGA1*-related retinopathy (MONDO:0800405). Eight variants (missense, nonsense, frameshift) that have been reported in 06 probands (and their families) in 5 publications (PMIDs: 7479749, 23462753, 12362048, 15570217, 36115851) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. There are 49 *CNGA1* pathogenic and likely pathogenic variants listed on ClinVar (09/20/2022). The mechanism of pathogenicity is reported to be LOF. This gene-disease relationship is also supported by functional studies in mice where homozygous *Cnga1* mice harboring a c.1526A>G (p.Tyr509Cys) mutation showed progressive loss of photoreceptors and retinal degeneration (PMID: 36115851). In summary, *CNGA1* is definitively associated with *CNGA1*-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification has been approved by the ClinGen Retina GCEP on October 6th, 2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013405
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CNGA1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001379270.1. 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 | 110 | 1 | 114 | ||
| missense | 4 | 20 | 266 | 13 | 1 | 304 |
| nonsense | 13 | 15 | 28 | |||
| start loss | 0 | |||||
| frameshift | 22 | 23 | 1 | 46 | ||
| splice donor/acceptor (+/-2bp) | 8 | 1 | 9 | |||
| Total | 39 | 66 | 271 | 123 | 2 | 501 |
Highest pathogenic variant AF is 0.0029052973
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001366199.1 | 8 | MANE Select | |
| Ensembl | ENSP00000426862.3 | 8 | MANE Select | |
| RefSeq | NP_000078.3 | 8 | Standard | |
| RefSeq | NP_001136036.2 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- cAMP signaling pathway - Homo sapiens (human)
- cGMP-PKG signaling pathway - Homo sapiens (human)
- Phototransduction - Homo sapiens (human)
- NO-cGMP-PKG mediated Neuroprotection
- Signaling by GPCR
Biological Process
- visual perception
- rhodopsin mediated signaling pathway
- regulation of rhodopsin mediated signaling pathway
- cation transmembrane transport
Molecular Function
- intracellular cAMP-activated cation channel activity
- intracellular cGMP-activated cation channel activity
- protein binding
- cGMP binding
Cellular Component
- plasma membrane
- integral component of plasma membrane
- photoreceptor outer segment membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000402813
- Coding exons
- 9
- Length
- 80696
- Individuals with no LoFs
- 124720
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 152
- Defined
- 124872
- p
- 0.000609
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.441 | 358 | 382 | 0.936 | 0.0000196 | 5026 |
| Missense (PolyPhen) | 160 | 166.34 | 0.9619 | 2206 | ||
| Synonymous | -0.0217 | 142 | 142 | 1.00 | 0.00000774 | 1387 |
| Loss of Function | 1.89 | 22 | 33.9 | 0.650 | 0.00000204 | 426 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0012 | 0.0012 | notable |
| Latino/Admixed American | 0.00070 | 0.00070 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.0018 | 0.0018 | notable |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00054 | 0.00054 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0.00099 | 0.00099 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Visual signal transduction is mediated by a G-protein coupled cascade using cGMP as second messenger. This protein can be activated by cyclic GMP which leads to an opening of the cation channel and thereby causing a depolarization of rod photoreceptors.;
- Disease
- DISEASE: Retinitis pigmentosa 49 (RP49) [MIM:613756]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:15570217, ECO:0000269|PubMed:7479749}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.133
Intolerance Scores
- LoFtool
- 0.340
- RVIS EVS
- -0.05
- RVIS percentile EVS
- 50.34
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.927
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |