GNAT2

protein-coding

G protein subunit alpha transducin 2, the group of G protein subunits alpha, group i

Gene summary

Transducin is a 3-subunit guanine nucleotide-binding protein (G protein) which stimulates the coupling of rhodopsin and cGMP-phoshodiesterase during visual impulses. The transducin alpha subunits in rods and cones are encoded by separate genes. This gene encodes the alpha subunit in cones. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001377295.2

Inheritance

AR, AD

ClinVar variants

P:45U:122B:64

Top phenotype

Achromatopsia 4

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr1:109,603,091-109,619,929

External References & Databases

Ensembl (ENSG00000134183)

Transcript & Mutation Effects

hg38 • Region Span ~16.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

achromatopsia 4MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013465

Submitter: Ambry Genetics

GNAT2-related retinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800392

Submitter: ClinGen

*GNAT2* was first reported in relation to autosomal recessive cases of achromatopsia 4 (ACHM) in 2002 (PMID: 12077706). In the complete form of ACHM, affected individuals typically present early in life with nystagmus, photophobia, low visual acuity, and total color blindness. Electroretinographic recordings (ERG) show an absent photopic and a normal scotopic response in affected individuals. Some individuals show residual color vision and slightly better visual acuity leading to a clinical diagnosis of incomplete ACHM. Because of the broad spectrum of potential phenotypes, these cases with causal variants in *GNAT2* have been curated under the inclusive disease name *GNAT2*-related retinopathy (MONDO:0800392). Ten suspected pathogenic variants were scored as part of this curation (four nonsense, two missense and four frameshift), which have been reported among twelve probands in seven publications (PMIDs:12077706, 12205108, 31058429, 27718025, 21107338, 32203983, 28041643). The mechanism of pathogenicity appears to be biallelic loss-of-function. Additionally, segregation data from two publications (PMIDs: 12205108, 21107338) were scored. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by experimental evidence that *GNAT2* is expressed in retina photoreceptor cells of developing zebrafish embryos (PMID: 22815753). A mouse model with a homozygous *GNAT2* mutation was shown to have little or no light-adapted (cone-mediated) ERG response and poor visual acuity, similar to observations in the human form of complete achromatopsia. Using AAV gene therapy to inject wild-type *GNAT2* cDNA into the retina of the mutated mice, the ERG response and visual acuity phenotypes were rescued (PMID: 17515894). In a naturally occurring mouse model with a different *GNAT2* mutation, affected mice displayed no cone ERG response, showed evidence of altered transducin protein structure and M-opsin mislocalization, and developed cone degeneration by 12 months of age (PMID: 23580486). In summary, *GNAT2* is definitively associated with autosomal recessive inheritance of *GNAT2*-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification according to the ClinGen template. This classification was approved by the ClinGen Retina GCEP on November 3rd, 2022 (SOP Version 9).

achromatopsia 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013465

Submitter: PanelApp Australia

achromatopsia 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013465

Submitter: Labcorp Genetics (formerly Invitae)

achromatopsia 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013465

Submitter: G2P

achromatopsiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018852

Submitter: Orphanet

cone dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000455

Submitter: Orphanet

Clinical Genomic Database (CGD)

Achromatopsia 4AR

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: 12205108; 12077706; 15557429; 21107338

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GNAT2 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 230

Achromatopsia 4Total: 54

not specifiedTotal: 29

Inborn genetic diseasesTotal: 28

GNAT2-related disorderTotal: 19

Retinal dystrophyTotal: 7

AchromatopsiaTotal: 3

Cone dystrophyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001377295.2. 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			6 clinvar	55 clinvar		61
missense	2 clinvar	4 clinvar	115 clinvar	8 clinvar	1 clinvar	130
nonsense	5 clinvar	4 clinvar				9
start loss		1 clinvar				1
frameshift	11 clinvar	6 clinvar	1 clinvar			18
splice donor/acceptor (+/-2bp)	3 clinvar	9 clinvar				12
Total	21	24	122	63	1	231

Highest pathogenic variant AF is 0.000014881488

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001377295.2	RefSeq	NP_001364224.1	8	MANE Select
ENST00000679935.1	Ensembl	ENSP00000505083.1	8	MANE Select
NM_001379232.1	RefSeq	NP_001366161.1	8	Standard
NM_005272.5	RefSeq	NP_005263.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
gnat2	Danio rerio	Structure: melanocyte Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

gnat2

Danio rerio

Structure: melanocyte

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Phototransduction - Homo sapiens (human)
Signaling by GPCR
Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding
Signaling by WNT
Signal Transduction

Biological Process

detection of chemical stimulus involved in sensory perception of bitter taste
protein folding
G protein-coupled receptor signaling pathway
adenylate cyclase-modulating G protein-coupled receptor signaling pathway
positive regulation of cytosolic calcium ion concentration

Molecular Function

G protein-coupled receptor binding
GTPase activity
GTP binding
G protein-coupled photoreceptor activity
G-protein beta/gamma-subunit complex binding

Cellular Component

photoreceptor outer segment
photoreceptor inner segment
heterotrimeric G-protein complex
plasma membrane
photoreceptor outer segment membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000351050
Coding exons: 8
Length: 9791
Individuals with no LoFs: 125718
Homozygous LoFs: 0
Heterozygous LoFs: 30
Defined: 125748
p: 0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.663	161	186	0.863	0.0000102	2372
Missense (PolyPhen)		71	82.227	0.86347		1099
Synonymous	0.0217	71	71.2	0.997	0.00000418	636
Loss of Function	1.62	11	18.6	0.593	0.00000118	215

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.00020	0.00020	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. Transducin is an amplifier and one of the transducers of a visual impulse that performs the coupling between rhodopsin and cGMP-phosphodiesterase.;

Recessive Scores

pRec: 0.168

Intolerance Scores

LoFtool: 0.303
RVIS EVS: 0.02
RVIS percentile EVS: 55.22

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0545

Gene Damage Prediction

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