CNGB3

protein-coding

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

Gene summary

This gene encodes the beta subunit of a cyclic nucleotide-gated ion channel. The encoded beta subunit appears to play a role in modulation of channel function in cone photoreceptors. This heterotetrameric channel is necessary for sensory transduction, and mutations in this gene have been associated with achromatopsia 3, progressive cone dystrophy, and juvenile macular degeneration, also known as Stargardt Disease. [provided by RefSeq, Feb 2010]

Previous symbols:

ACHM3
ACHM1
RMCH

MANE transcript

NM_019098.5

Inheritance

AD, AR

ClinVar variants

P:321U:402B:358

Top phenotype

Achromatopsia 3; Macular degeneration, juvenile

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr8:86,553,977-86,743,675

External References & Databases

Ensembl (ENSG00000170289)

Transcript & Mutation Effects

hg38 • Region Span ~189.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cone dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000455

Submitter: Orphanet

severe early-childhood-onset retinal dystrophyLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0009549

Submitter: Labcorp Genetics (formerly Invitae)

achromatopsiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018852

Submitter: Orphanet

achromatopsia 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009875

Submitter: Natera

achromatopsia 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009875

Submitter: G2P

achromatopsia 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009875

Submitter: Labcorp Genetics (formerly Invitae)

CNGB3-related retinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100446

Submitter: ClinGen

The CNGB3 gene was first reported in relation to autosomal recessive CNB3-related retinopathy in 2000 in an individual described as having achromatopsia (Sundin et. Al., 2000; PMID 10888875). Achromatopsia is characterized by photophobia, reduced visual acuity, nystagmus, and inability to discriminate between colors. Electroretinogram shows an absent cone response whereas rod function is preserved. This condition was curated under the disesae entity "CNGB3-related retinopathy". The maximum score for genetic evidence was achieved by the addition of 5 variants (PMID:10888875, 15657609, 31544997) in this curation, however there is more evidence available in the literature. There are over 200 CNGB3 pathogenic and likely pathogenic variants listed on ClinVar (10/05/2021). In one report (PMID 15657609), a cohort of 341 unrelated patients with achromatopsia was studied which resulted in identification of disease-causing variants in 163 patients. Among them, 105 were homozygous for the variant while 44 were compound heterozygotes, 14 carried a single allele. Another study reported a deep intronic variant NM_019098.4(CNGB3):c.1663-1205G>A in-trans with pathogenic variants in 18 patients with achromatopsia, making this variant one of the most frequent variant associated with achromatopsia (PMID 31544997). CNGB3 and CNGA3 proteins were found to be highly expressed in NRL-/- mouse retinas by western blotting and immunolabeling. Moreover, both these cone CNG channels were observed to co-localize in S and M cones (PMID 18665891). Mouse studies also supported the role of Cngb3 in cone function. A mice line with naturally occurring missense variant NM_013927:c.692G>A; p.(R231H) was studied for visual function which revealed that homozygous mice (n=12) had lost cone function while their rod function was intact (PMID 30592498). Additionally, in another knockout mouse study, homozygous null mice recapitulated achromatopsia phenotype, briefly by showing a decrease in photopic ERG responses, visual acuity, and cone density (PMID 19767295). Role of CNGB3 in cone function was also further supported by rescue studies in null mice by sub-retinal injections of AAV8(Y447,&33F) constructs. The transgenic mice showed expression of CNGB3 in cone cells and restored photopic ERG responses (PMID 32305965). In summary, CNGB3 is definitively associated with autosomal recessive CNGB3-related retinopathy. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Achromatopsia 3; Macular degeneration, juvenileAR

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: 4192495; 1347967; 10888875; 15712225; 17265047; 17652762; 19767295; 20454696; 23362848

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CNGB3 variants in ClinVar

18 Conditions Cataloged

not providedTotal: 1124

Achromatopsia 3Total: 297

AchromatopsiaTotal: 254

CNGB3-related disorderTotal: 123

not specifiedTotal: 110

Inborn genetic diseasesTotal: 107

Severe early-childhood-onset retinal dystrophyTotal: 56

Retinal dystrophyTotal: 39

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019098.5. 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			12 clinvar	314 clinvar	2 clinvar	328
missense	4 clinvar	18 clinvar	380 clinvar	34 clinvar	3 clinvar	439
nonsense	55 clinvar	22 clinvar	3 clinvar	3 clinvar		83
start loss		3 clinvar				3
frameshift	91 clinvar	54 clinvar	4 clinvar	2 clinvar		151
splice donor/acceptor (+/-2bp)	19 clinvar	55 clinvar	3 clinvar			77
Total	169	152	402	353	5	1081

Highest pathogenic variant AF is 0.0022731433

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_019098.5	RefSeq	NP_061971.3	18	MANE Select
ENST00000320005.6	Ensembl	ENSP00000316605.5	18	MANE Select
ENST00000517327.5	Ensembl	ENSP00000428329.1	3	Standard
ENST00000681746.1	Ensembl	ENSP00000505959.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

cation transport
signal transduction
visual perception
cation transmembrane transport

Molecular Function

intracellular cAMP-activated cation channel activity
intracellular cGMP-activated cation channel activity
cGMP binding

Cellular Component

photoreceptor outer segment
transmembrane transporter complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000320005
Coding exons: 18
Length: 189699
Individuals with no LoFs: 125081
Homozygous LoFs: 2
Heterozygous LoFs: 665
Defined: 125748
p: 0.00266

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.18	485	417	1.16	0.0000221	5289
Missense (PolyPhen)		107	99.568	1.0746		1321
Synonymous	-0.619	160	150	1.06	0.00000846	1527
Loss of Function	1.46	34	44.5	0.765	0.00000246	555

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00087	0.00086	rare
Latino/Admixed American	0.0043	0.0043	notable
Ashkenazi Jewish	0.0014	0.0014	notable
East Asian	0.00071	0.00071	rare
Finnish	0.0028	0.0028	notable
European (Non-Finnish)	0.0033	0.0033	notable
South Asian	0.00092	0.00091	rare
Other	0.0029	0.0029	notable

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 cGMP which leads to an opening of the cation channel and thereby causing a depolarization of rod 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 efficiency of the channel when coexpressed with CNGA3 (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 3 (ACHM3) [MIM:262300]: 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. Achromatopsia type 3 patients manifest severe myopia. {ECO:0000269|PubMed:10888875, ECO:0000269|PubMed:10958649, ECO:0000269|PubMed:12357335, ECO:0000269|PubMed:14757870, ECO:0000269|PubMed:15657609, ECO:0000269|PubMed:15712225}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.221
RVIS EVS: 1.67
RVIS percentile EVS: 96.33

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.256

Gene Damage Prediction

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