AGRN

agrin, the group of Proteoglycans

Basic information

Region (hg38): 1:1020120-1056119

Previous symbols: [ "AGRIN" ]

Links

ENSG00000188157 ∙ NCBI:375790 ∙ OMIM:103320 ∙ HGNC:329 ∙ Uniprot:O00468 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• congenital myasthenic syndrome 8 (Strong), mode of inheritance: AR
• congenital myasthenic syndrome 8 (Strong), mode of inheritance: AR
• postsynaptic congenital myasthenic syndrome (Supportive), mode of inheritance: AR
• presynaptic congenital myasthenic syndrome (Supportive), mode of inheritance: AD
• congenital myasthenic syndrome 8 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Myasthenic syndrome, congenital 8	AR	Musculoskeletal; Neurologic; Pharmacogenomic	Ephedrine treatment has been reported as effective in affected inviduals; Medical treatment with acetylcholine esterase inhibitors and/or potassium channel blocker 3,4-diaminopyridine may be beneficial in many individuals; In infancy, the use of apnea monitors may be indicated; Agents that affect neuromuscular transmission and exacerbate myasthenic manifestations should be avoided	Musculoskeletal; Neurologic	19631309; 20301347; 22205389; 22678886

ClinVar

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

• Congenital myasthenic syndrome 8 (24 variants)
• Abnormality of the musculature (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the AGRN 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	598	20	629
missense		3	946	44	6	999
nonsense	8	2	2			12
start loss						0
frameshift	17	4				21
inframe indel			16			16
splice donor/acceptor (+/-2bp)		11				11
splice region		1	40	69	4	114
non coding			6	247	82	335
Total	25	20	981	889	108

Highest pathogenic variant AF is 0.0000525

Variants in AGRN

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

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

Position	Type	Phenotype	Significance	ClinVar
1-1020177-C-A		Congenital myasthenic syndrome 8	Uncertain significance (Jan 15, 2024)
1-1020182-C-T		Congenital myasthenic syndrome 8	Uncertain significance (Jul 09, 2020)
1-1020183-G-C		Congenital myasthenic syndrome 8 • AGRN-related disorder	Benign (Jan 26, 2024)
1-1020192-C-G		Congenital myasthenic syndrome 8	Uncertain significance (Jul 19, 2022)
1-1020192-C-T		Congenital myasthenic syndrome 8	Uncertain significance (Mar 01, 2022)
1-1020193-G-T		Congenital myasthenic syndrome 8	Likely benign (Nov 12, 2022)
1-1020195-G-C		Congenital myasthenic syndrome 8	Uncertain significance (May 10, 2022)
1-1020196-C-T		Congenital myasthenic syndrome 8	Likely benign (Feb 27, 2023)
1-1020196-CCCGCTGCGG-C		Congenital myasthenic syndrome 8	Uncertain significance (May 18, 2022)
1-1020199-G-A		Congenital myasthenic syndrome 8	Likely benign (Mar 09, 2022)
1-1020200-C-A		Congenital myasthenic syndrome 8	Uncertain significance (Mar 18, 2022)
1-1020200-C-T		Congenital myasthenic syndrome 8	Likely benign (Dec 22, 2019)
1-1020204-G-A		Congenital myasthenic syndrome 8	Uncertain significance (Jul 30, 2023)
1-1020204-G-T		Inborn genetic diseases	Uncertain significance (Sep 01, 2021)
1-1020204-G-GGCCGCTGCT		Congenital myasthenic syndrome 8	Uncertain significance (Jan 09, 2024)
1-1020206-C-T		Congenital myasthenic syndrome 8	Uncertain significance (Mar 26, 2022)
1-1020208-G-A		Congenital myasthenic syndrome 8	Likely benign (Nov 04, 2023)
1-1020208-G-C		Congenital myasthenic syndrome 8	Likely benign (Mar 18, 2022)
1-1020209-C-G		Congenital myasthenic syndrome 8	Uncertain significance (Mar 08, 2022)
1-1020216-C-G			Uncertain significance (May 19, 2020)
1-1020216-C-T		Congenital myasthenic syndrome 8	Uncertain significance (Aug 31, 2021)
1-1020216-CG-GT		Congenital myasthenic syndrome 8	Uncertain significance (Oct 24, 2022)
1-1020217-G-T		not specified • Congenital myasthenic syndrome 8	Benign (Feb 01, 2024)
1-1020220-C-T		Congenital myasthenic syndrome 8	Likely benign (Jan 26, 2024)
1-1020221-C-T		Congenital myasthenic syndrome 8	Uncertain significance (Mar 26, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
AGRN	protein_coding	protein_coding	ENST00000379370	36	35994

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
5.47e-7	1.00	125566	0	64	125630	0.000255

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.226	1303	1.33e+3	0.983	0.0000995	12779
Missense in Polyphen		342	394.87	0.86611		3727
Synonymous	-3.96	727	603	1.20	0.0000496	4373
Loss of Function	6.01	29	90.9	0.319	0.00000500	963

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000715	0.000702
Ashkenazi Jewish	0.000411	0.000397
East Asian	0.000166	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.000320	0.000299
Middle Eastern	0.000166	0.000163
South Asian	0.000137	0.000131
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Isoform 1: heparan sulfate basal lamina glycoprotein that plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ) and directs key events in postsynaptic differentiation. Component of the AGRN-LRP4 receptor complex that induces the phosphorylation and activation of MUSK. The activation of MUSK in myotubes induces the formation of NMJ by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane. Calcium ions are required for maximal AChR clustering. AGRN function in neurons is highly regulated by alternative splicing, glycan binding and proteolytic processing. Modulates calcium ion homeostasis in neurons, specifically by inducing an increase in cytoplasmic calcium ions. Functions differentially in the central nervous system (CNS) by inhibiting the alpha(3)- subtype of Na+/K+-ATPase and evoking depolarization at CNS synapses. This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain.; FUNCTION: Isoform 1, isoform 4 and isoform 5: neuron-specific (z+) isoforms that contain C-terminal insertions of 8-19 AA are potent activators of AChR clustering. Isoform 5, agrin (z+8), containing the 8-AA insert, forms a receptor complex in myotubules containing the neuronal AGRN, the muscle-specific kinase MUSK and LRP4, a member of the LDL receptor family. The splicing factors, NOVA1 and NOVA2, regulate AGRN splicing and production of the 'z' isoforms.; FUNCTION: Agrin N-terminal 110 kDa subunit: is involved in regulation of neurite outgrowth probably due to the presence of the glycosaminoglcan (GAG) side chains of heparan and chondroitin sulfate attached to the Ser/Thr- and Gly/Ser-rich regions. Also involved in modulation of growth factor signaling (By similarity). {ECO:0000250, ECO:0000269|PubMed:19631309, ECO:0000269|PubMed:21969364}.
• Disease: DISEASE: Myasthenic syndrome, congenital, 8 (CMS8) [MIM:615120]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness. CMS8 is an autosomal recessive disease characterized by prominent defects of both the pre- and postsynaptic regions. Affected individuals have onset of muscle weakness in early childhood; the severity of the weakness and muscles affected is variable. {ECO:0000269|PubMed:19631309, ECO:0000269|PubMed:22205389, ECO:0000269|PubMed:24951643}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: ECM-receptor interaction - Homo sapiens (human);Primary Focal Segmental Glomerulosclerosis FSGS;Splicing factor NOVA regulated synaptic proteins;Developmental Biology;Signaling by GPCR;Signal Transduction;Metabolism of fat-soluble vitamins;Metabolism of carbohydrates;A tetrasaccharide linker sequence is required for GAG synthesis;HS-GAG biosynthesis;HS-GAG degradation;Heparan sulfate/heparin (HS-GAG) metabolism;Integrin cell surface interactions;Chondroitin sulfate/dermatan sulfate metabolism;Glycosaminoglycan metabolism;Extracellular matrix organization;Metabolism;Metabolism of vitamins and cofactors;Integrin;role of nicotinic acetylcholine receptors in the regulation of apoptosis;agrin in postsynaptic differentiation;NCAM signaling for neurite out-growth;Retinoid metabolism and transport;NCAM1 interactions;Non-integrin membrane-ECM interactions;G alpha (i) signalling events;Axon guidance;Visual phototransduction;ECM proteoglycans;GPCR downstream signalling;Wnt Canonical;Wnt Mammals (Consensus)

Recessive Scores

• pRec: 0.645

Intolerance Scores

• loftool: 0.421
• rvis_EVS: -0.22
• rvis_percentile_EVS: 37.33

Haploinsufficiency Scores

• pHI: 0.402
• hipred: Y
• hipred_score: 0.637
• ghis: 0.573

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.883

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Agrn
• Phenotype: growth/size/body region phenotype; homeostasis/metabolism phenotype; muscle 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; renal/urinary system phenotype; limbs/digits/tail 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)

Zebrafish Information Network

• Gene name: agrn
• Affected structure: CaP motoneuron
• Phenotype tag: abnormal
• Phenotype quality: decreased length

Gene ontology

• Biological process: retinoid metabolic process;glycosaminoglycan biosynthetic process;glycosaminoglycan catabolic process;cytoskeleton organization;signal transduction;G protein-coupled acetylcholine receptor signaling pathway;extracellular matrix organization;receptor clustering;positive regulation of GTPase activity;clustering of voltage-gated sodium channels;positive regulation of synaptic growth at neuromuscular junction;positive regulation of transcription by RNA polymerase II;synapse organization;positive regulation of filopodium assembly
• Cellular component: extracellular region;basement membrane;Golgi lumen;cytosol;plasma membrane;integral component of membrane;cell junction;lysosomal lumen;synapse;collagen-containing extracellular matrix;extracellular exosome
• Molecular function: dystroglycan binding;structural constituent of cytoskeleton;extracellular matrix structural constituent;calcium ion binding;protein binding;sialic acid binding;chondroitin sulfate binding;laminin binding;heparan sulfate proteoglycan binding