GeneBe

CNGA3

protein-coding

cyclic nucleotide gated channel subunit alpha 3, the group of Cyclic nucleotide gated channels

Gene summary

This gene encodes a member of the cyclic nucleotide-gated cation channel protein family which is required for normal vision and olfactory signal transduction. Mutations in this gene are associated with achromatopsia (rod monochromacy) and color blindness. Two alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

Previous symbols:
  • CNCG3
  • ACHM2

MANE transcript

NM_001298.3

Inheritance

AR, AD

ClinVar variants

P:275U:298B:203

Top phenotype

Achromatopsia 2; Leber congenital amaurosis

gnomAD constraint

pLI —, LoF o/e 1.08

Max pathogenic AF

—

Genomic locus

chr2:98,346,188-98,398,601

External References & Databases

Ensembl (ENSG00000144191)NCBI Gene (1261)OMIM (600053)HGNC:2150GenCCUniProt (Q16281)AlphaFoldClinVar (CNGA3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~52.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

achromatopsia 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009003

Submitter: Illumina

achromatopsia 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009003

Submitter: G2P

achromatopsiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018852

Submitter: Orphanet

cone-rod dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: Orphanet

achromatopsia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009003

Submitter: Labcorp Genetics (formerly Invitae)

CNGA3-related retinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800102

Submitter: ClinGen

CNGA3 was first reported in relation to autosomal recessive CNGA3-related retinopathy, in a patient with achromatopsia (OMIM:216900) in 1998 (PMID: 9721202). Achromatopsia is a rare congenital autosomal recessive disorder characterized by photophobia, reduced visual acuity, nystagmus, and the complete inability to discriminate between colors. Later studies showed that patients with biallelic pathogenic CNGA3 variants can also have cone-rod dystrophy (PMID: 24903488; PMID: 11536077). Based on the ClinGen Lumping and Splitting guidelines, these disorders are lumped together as CNGA3-related retinopathy. 15 variants (missense, nonsense, frameshift) that have been reported in 11 probands are included in this curation (PMID: 9662398; 27624628; 25637600; 24903488; 25052312). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Notably, four variants (p.R277C, p.R283W, p.R435W, and p.F547L) were reported to account for >40% of all detected variants (PMID: 11536077). Biallelic CNGA3 variants have been demonstrated to segregated in at least 5 families with three or more affected individuals (PMID: 9662398; 25637600; 24903488; 25052312). The mechanism of pathogenicity appears to be loss-of-function. In-vitro studies demonstrated that decreased expression of CNGA3 in the cell membrane of p.Cys319Arg knock-in HEK293 cells possibly as a result of reduced protein stability (PMID: 25052312). In the Muraki-Oda et al study, they identified 32 missense CNGA3 variants with ablated channel functions in an in-vitro study (PMID:17693388). In the Paylou et al study using a CNGA3-/-mouse model, the achromatopsia phenotype was rescued using intravitreal CNGA3 delivery using AAV2.GL, leading to cone-specific expression of CNGA3 protein. In summary, CNGA3 is definitively associated with autosomal recessive CNGA3-related retinopathy. This has been repeated demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Achromatopsia 2; Leber congenital amaurosisAR

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: 9662398; 11536077; 15059731; 15980212; 16961972; 18636117; 20454696; 21901789; 21911670; 21912902; 23362848; 25616768Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CNGA3 variants in ClinVar

22 Conditions Cataloged
not providedTotal: 677
Achromatopsia 2Total: 205
not specifiedTotal: 110
CNGA3-related disordersTotal: 107
CNGA3-related disorderTotal: 96
Inborn genetic diseasesTotal: 84
Retinal dystrophyTotal: 44
AchromatopsiaTotal: 37

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001298.3. 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.

EffectPLPVUSLBBSum
synonymous
5
clinvar
166
clinvar
2
clinvar
 173
missense
43
clinvar
115
clinvar
284
clinvar
35
clinvar
 477
nonsense
16
clinvar
32
clinvar
2
clinvar
 50
start loss
2
clinvar
 2
frameshift
30
clinvar
28
clinvar
3
clinvar
 61
splice donor/acceptor (+/-2bp)
4
clinvar
7
clinvar
2
clinvar
 13
Total931822982012776

Highest pathogenic variant AF is 0.00051240745

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001298.3RefSeqNP_001289.17MANE Select
ENST00000272602.7EnsemblENSP00000272602.27MANE Select
NM_001079878.2RefSeqNP_001073347.16Standard
ENST00000436404.6EnsemblENSP00000410070.26Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • cAMP signaling pathway - Homo sapiens (human)
  • Olfactory transduction - Homo sapiens (human)
  • NO-cGMP-PKG mediated Neuroprotection
  • Visual signal transduction: Cones

Biological Process

  • cation transport
  • signal transduction
  • visual perception
  • response to corticosteroid
  • response to magnesium ion

Molecular Function

  • intracellular cAMP-activated cation channel activity
  • intracellular cGMP-activated cation channel activity
  • protein C-terminus binding
  • ligand-gated ion channel activity
  • cGMP binding

Cellular Component

  • cytoplasm
  • plasma membrane
  • dendrite
  • axon initial segment
  • perikaryon

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000393504
Coding exons
7
Length
52447
Individuals with no LoFs
125612
Homozygous LoFs
0
Heterozygous LoFs
136
Defined
125748
p
0.000541
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.03684044021.010.00002574535
Missense (PolyPhen)119124.980.952171443
Synonymous-0.4051831761.040.00001171392
Loss of Function-0.3972825.81.080.00000139301

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000310.00031rare
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish0.00580.0058notable
East Asian0.000650.00065rare
Finnish0.000140.00014rare
European (Non-Finnish)0.000330.00033rare
South Asian0.000360.00036rare
Other0.000980.00098rare

dbNSFP Gene Annotations

Source: dbNSFP

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 cone photoreceptors. Induced a flickering channel gating, weakened the outward rectification in the presence of extracellular calcium, increased sensitivity for L-cis diltiazem and enhanced the cAMP efficacy of the channel when coexpressed with CNGB3 (By similarity). Essential for the generation of light-evoked electrical responses in the red-, green- and blue sensitive cones. {ECO:0000250, ECO:0000269|PubMed:10888875}.;
Disease
DISEASE: Achromatopsia 2 (ACHM2) [MIM:216900]: An autosomal recessive, ocular stationary disorder due to the absence of functioning cone photoreceptors in the retina. It is characterized by total colorblindness, low visual acuity, photophobia and nystagmus. {ECO:0000269|PubMed:11536077, ECO:0000269|PubMed:14757870, ECO:0000269|PubMed:15712225, ECO:0000269|PubMed:15743887, ECO:0000269|PubMed:18521937, ECO:0000269|PubMed:24903488, ECO:0000269|PubMed:26493561, ECO:0000269|PubMed:9662398}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.183

Intolerance Scores

LoFtool
0.0506
RVIS EVS
-0.66
RVIS percentile EVS
16.12

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.296

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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