AGO2

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

Basic information

Region (hg38): 8:140520156-140635633

Previous symbols: [ "EIF2C2", "CASC7" ]

Links

ENSG00000123908 ∙ NCBI:27161 ∙ OMIM:606229 ∙ HGNC:3263 ∙ Uniprot:Q9UKV8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Lessel-Kreienkamp syndrome (Strong), mode of inheritance: AD
• Lessel-Kreienkamp syndrome (Strong), mode of inheritance: AD
• Lessel-Kreienkamp syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Lessel-Kreienkamp syndrome	AD	Cardiovascular	Some individuals have been described with congenital cardiac anomalies, and awareness may allow early identification and management	Cardiovascular; Craniofacial; Musculoskeletal; Neurologic	33199684

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the AGO2 gene.

• Lessel-Kreienkamp syndrome (2 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the AGO2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				11	7	18
missense	2	8	49	1		60
nonsense		1	4			5
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			2	4	2	8
non coding					4	4
Total	2	9	54	12	11

Variants in AGO2

This is a list of pathogenic ClinVar variants found in the AGO2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
8-140532105-T-TG			Uncertain significance (Dec 29, 2023)
8-140532112-C-G		Inborn genetic diseases	Uncertain significance (Jan 16, 2024)
8-140532145-C-A		Premature ovarian failure 3	Likely pathogenic (Oct 10, 2022)
8-140532426-C-T		Lessel-Kreienkamp syndrome	Uncertain significance (Jan 31, 2023)
8-140532435-C-T		not specified	Uncertain significance (May 28, 2024)
8-140532474-A-G			Uncertain significance (Jun 09, 2022)
8-140532495-A-G		AGO2-related disorder	Uncertain significance (Apr 19, 2023)
8-140532498-C-T		Lessel-Kreienkamp syndrome	Likely pathogenic (Apr 05, 2022)
8-140532499-G-A			Likely benign (Dec 01, 2023)
8-140532512-C-T			Uncertain significance (Jan 31, 2024)
8-140532522-T-G			Uncertain significance (Jan 02, 2022)
8-140532592-A-C		Inborn genetic diseases	Uncertain significance (Sep 27, 2021)
8-140532593-T-C			Uncertain significance (Nov 23, 2022)
8-140535479-C-T		Inborn genetic diseases	Uncertain significance (Jan 23, 2024)
8-140535487-C-T		Lessel-Kreienkamp syndrome • Inborn genetic diseases	Pathogenic/Likely pathogenic (Mar 01, 2022)
8-140535510-G-A			Likely benign (Apr 01, 2024)
8-140535527-T-A		AGO2-related disorder	Uncertain significance (May 18, 2023)
8-140535542-C-G		Lessel-Kreienkamp syndrome	Pathogenic (Jan 20, 2021)
8-140539313-A-G			Benign (May 08, 2018)
8-140539349-G-A		Neurodevelopmental disorder	Pathogenic/Likely pathogenic (Feb 22, 2024)
8-140539376-T-C			Uncertain significance (Dec 28, 2023)
8-140539462-T-C			Likely benign (May 01, 2023)
8-140541211-G-A			Uncertain significance (Nov 25, 2022)
8-140541225-C-T			Uncertain significance (May 17, 2023)
8-140541227-C-T			Likely benign (Jan 01, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
AGO2	protein_coding	protein_coding	ENST00000220592	19	104455

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	4.66e-7	125745	0	2	125747	0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	6.06	162	568	0.285	0.0000385	5643
Missense in Polyphen		15	177.78	0.084375		1792
Synonymous	0.904	225	243	0.926	0.0000188	1665
Loss of Function	6.07	1	44.9	0.0223	0.00000227	495

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.00000879	0.00000879
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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}.
• Pathway: Competing endogenous RNAs (ceRNAs) regulate PTEN translation;Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;Pre-NOTCH Transcription and Translation;Pre-NOTCH Expression and Processing;Signaling by NOTCH;TP53 Regulates Metabolic Genes;Regulation of PTEN mRNA translation;PTEN Regulation;PIP3 activates AKT signaling;Signaling by Nuclear Receptors;Transcriptional Regulation by TP53;Regulation of RUNX1 Expression and Activity;Estrogen-dependent gene expression;Transcriptional regulation by small RNAs;ESR-mediated signaling;Intracellular signaling by second messengers;MicroRNA (miRNA) biogenesis;Transcriptional regulation by RUNX1;Small interfering RNA (siRNA) biogenesis;Post-transcriptional silencing by small RNAs;Gene Silencing by RNA (Consensus)

Recessive Scores

• pRec: 0.138

Intolerance Scores

• rvis_EVS: -1.42
• rvis_percentile_EVS: 4.1

Haploinsufficiency Scores

• pHI: 0.699
• hipred: Y
• hipred_score: 0.825
• ghis: 0.499

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: N

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ago2
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); embryo phenotype; immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Zebrafish Information Network

• Gene name: ago2
• Affected structure: nucleate erythrocyte
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: translation;translational initiation;Wnt signaling pathway, calcium modulating pathway;post-embryonic development;RNA secondary structure unwinding;miRNA metabolic process;positive regulation of gene expression;negative regulation of gene expression;production of siRNA involved in RNA interference;gene silencing by RNA;pre-miRNA processing;siRNA loading onto RISC involved in RNA interference;posttranscriptional gene silencing by RNA;production of miRNAs involved in gene silencing by miRNA;miRNA mediated inhibition of translation;mRNA cleavage involved in gene silencing by miRNA;miRNA loading onto RISC involved in gene silencing by miRNA;positive regulation of angiogenesis;positive regulation of transcription by RNA polymerase II;negative regulation of translational initiation;positive regulation of nuclear-transcribed mRNA poly(A) tail shortening;regulation of gene silencing by miRNA;RNA phosphodiester bond hydrolysis, endonucleolytic;mRNA cleavage involved in gene silencing by siRNA;positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay;positive regulation of trophoblast cell migration;positive regulation of miRNA mediated inhibition of translation
• Cellular component: P-body;nucleus;nucleoplasm;cytoplasm;cytosol;polysome;mRNA cap binding complex;membrane;RISC complex;cell junction;dendrite;micro-ribonucleoprotein complex;extracellular exosome;RISC-loading complex;ribonucleoprotein complex
• Molecular function: RNA 7-methylguanosine cap binding;RNA polymerase II complex binding;core promoter binding;RNA binding;double-stranded RNA binding;single-stranded RNA binding;translation initiation factor activity;endoribonuclease activity;protein binding;protein C-terminus binding;siRNA binding;miRNA binding;metal ion binding;endoribonuclease activity, cleaving siRNA-paired mRNA;endoribonuclease activity, cleaving miRNA-paired mRNA;mRNA cap binding