GeneBe

AGO2

protein-coding

argonaute RISC catalytic component 2, the group of Argonaute RISC component family|RISC loading complex|Endoribonucleases

Gene summary

This gene encodes a member of the Argonaute family of proteins which play a role in RNA interference. The encoded protein is highly basic, and contains a PAZ domain and a PIWI domain. It may interact with dicer1 and play a role in short-interfering-RNA-mediated gene silencing. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

Previous symbols:
  • EIF2C2
  • CASC7

MANE transcript

NM_012154.5

Inheritance

AD

ClinVar variants

P:20U:146B:36

Top phenotype

Lessel-Kreienkamp syndrome

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr8:140,520,156-140,635,633

External References & Databases

Ensembl (ENSG00000123908)NCBI Gene (27161)OMIM (606229)HGNC:3263GenCCUniProt (Q9UKV8)AlphaFoldClinVar (AGO2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~115.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Lessel-Kreienkamp syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030897

Submitter: Labcorp Genetics (formerly Invitae)

Lessel-Kreienkamp syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0030897

Submitter: ClinGen

The AGO2 gene is located on chromosome 8 at 8q24.3 and encodes the argonaute RISC catalytic component 2, which is associated with RNA-mediated gene silencing as part of the RNA-inducing silencing complex (RISC). The AGO2 gene was first reported in relation to autosomal dominant Lessel-Kreienkamp syndrome in 2020 (Lessel et al., PMID: 33199684). At least 12 unique variants (including 11 missense and an in-frame deletion) have been reported in over 20 individuals and included in this curation (PMID: 33199684; van der Ven et al., 2021, PMID: 34490615; Stutterd et al., 2022, PMID: 35803560). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Evidence supporting this gene-disease relationship is primarily case level evidence. Experimental evidence includes biochemical function, a non-human model organism, and functional alteration of non-patient cells. Variants in AGO1 and deletions encompassing AGO1 and AGO3 that belong to the same Argonaute family of proteins as AGO2, have been reported in association with neurodevelopmental phenotypes (Tokita et al., 2015, PMID: 25271087; Schalk et al., 2022, PMID: 34930816). AGO2 has been functionally linked to the FMR1 gene associated with Fragile X syndrome, which displays similar phenotypes to those observed in Lessel-Kreienkamp syndrome (Jin et al., 2004, PMID: 14703574; Pepper et al,. 2009, PMID: 19888420). D. melanogaster Ago2 mutants show neurological deficits and present with defective neuronal branching and synapse formation (19888420). In summary, there is definitive evidence to support the relationship between AGO2 and autosomal dominant Lessel-Kreienkamp syndrome. This relationship 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 Syndromic Disorders GCEP on the meeting date 15th September 2023 (SOP Version 9.0).

Lessel-Kreienkamp syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030897

Submitter: Illumina

Lessel-Kreienkamp syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030897

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Lessel-Kreienkamp syndromeAD

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: Some individuals have been described with congenital cardiac anomalies, and awareness may allow early identification and management

Refs: 33199684Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AGO2 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 136
Inborn genetic diseasesTotal: 36
Lessel-Kreienkamp syndromeTotal: 35
not specifiedTotal: 13
AGO2-related disorderTotal: 11
Neurodevelopmental disorderTotal: 1
Premature ovarian failure 3Total: 1
See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012154.5. 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.

EffectPLPVUSLBBSum
synonymous
4
clinvar
29
clinvar
5
clinvar
 38
missense
3
clinvar
16
clinvar
126
clinvar
2
clinvar
 147
nonsense
1
clinvar
8
clinvar
 9
start loss
0
frameshift
3
clinvar
 3
splice donor/acceptor (+/-2bp)
5
clinvar
 5
Total317146315202

Highest pathogenic variant AF is 0.0000020521547

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_012154.5RefSeqNP_036286.219MANE Select
ENST00000220592.10EnsemblENSP00000220592.519MANE Select
NM_001164623.3RefSeqNP_001158095.118Standard
ENST00000519980.5EnsemblENSP00000430176.118Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
ago2Danio rerio

Structure: nucleate erythrocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Competing endogenous RNAs (ceRNAs) regulate PTEN translation
  • Signal Transduction
  • Gene expression (Transcription)
  • Generic Transcription Pathway
  • RNA Polymerase II Transcription

Biological Process

  • translation
  • translational initiation
  • Wnt signaling pathway, calcium modulating pathway
  • post-embryonic development
  • RNA secondary structure unwinding

Molecular Function

  • RNA 7-methylguanosine cap binding
  • RNA polymerase II complex binding
  • core promoter binding
  • RNA binding
  • double-stranded RNA binding

Cellular Component

  • P-body
  • nucleus
  • nucleoplasm
  • cytoplasm
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000220592
Coding exons
19
Length
104455
Individuals with no LoFs
125745
Homozygous LoFs
0
Heterozygous LoFs
2
Defined
125747
p
0.00000795
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense6.061625680.2850.00003855643
Missense (PolyPhen)15177.780.0843751792
Synonymous0.9042252430.9260.00001881665
Loss of Function6.07144.90.02230.00000227495

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish00.0absent
European (Non-Finnish)0.00000880.0000088rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Required for RNA-mediated gene silencing (RNAi) by the RNA-induced silencing complex (RISC). The 'minimal RISC' appears to include AGO2 bound to a short guide RNA such as a microRNA (miRNA) or short interfering RNA (siRNA). These guide RNAs direct RISC to complementary mRNAs that are targets for RISC-mediated gene silencing. The precise mechanism of gene silencing depends on the degree of complementarity between the miRNA or siRNA and its target. Binding of RISC to a perfectly complementary mRNA generally results in silencing due to endonucleolytic cleavage of the mRNA specifically by AGO2. Binding of RISC to a partially complementary mRNA results in silencing through inhibition of translation, and this is independent of endonuclease activity. May inhibit translation initiation by binding to the 7-methylguanosine cap, thereby preventing the recruitment of the translation initiation factor eIF4-E. May also inhibit translation initiation via interaction with EIF6, which itself binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit. The inhibition of translational initiation leads to the accumulation of the affected mRNA in cytoplasmic processing bodies (P-bodies), where mRNA degradation may subsequently occur. In some cases RISC-mediated translational repression is also observed for miRNAs that perfectly match the 3' untranslated region (3'-UTR). Can also up-regulate the translation of specific mRNAs under certain growth conditions. Binds to the AU element of the 3'-UTR of the TNF (TNF-alpha) mRNA and up-regulates translation under conditions of serum starvation. Also required for transcriptional gene silencing (TGS), in which short RNAs known as antigene RNAs or agRNAs direct the transcriptional repression of complementary promoter regions. {ECO:0000250|UniProtKB:Q8CJG0, ECO:0000255|HAMAP-Rule:MF_03031, ECO:0000269|PubMed:15105377, ECO:0000269|PubMed:15260970, ECO:0000269|PubMed:15284456, ECO:0000269|PubMed:15337849, ECO:0000269|PubMed:15800637, ECO:0000269|PubMed:16081698, ECO:0000269|PubMed:16142218, ECO:0000269|PubMed:16271387, ECO:0000269|PubMed:16289642, ECO:0000269|PubMed:16357216, ECO:0000269|PubMed:16756390, ECO:0000269|PubMed:16936728, ECO:0000269|PubMed:17382880, ECO:0000269|PubMed:17507929, ECO:0000269|PubMed:17524464, ECO:0000269|PubMed:17531811, ECO:0000269|PubMed:17932509, ECO:0000269|PubMed:18048652, ECO:0000269|PubMed:18178619, ECO:0000269|PubMed:18690212, ECO:0000269|PubMed:18771919, ECO:0000269|PubMed:19167051, ECO:0000269|PubMed:23746446}.;

Recessive Scores

pRec
0.138

Intolerance Scores

RVIS EVS
-1.42
RVIS percentile EVS
4.1

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
N

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumLowLow
Primary ImmunodeficiencyMediumLowMedium
CancerMediumLowMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.