AFG3L2

AFG3 like matrix AAA peptidase subunit 2, the group of AAA ATPases

Basic information

Region (hg38): 18:12328943-12377227

Previous symbols: [ "SCA28" ]

Links

ENSG00000141385 ∙ NCBI:10939 ∙ OMIM:604581 ∙ HGNC:315 ∙ Uniprot:Q9Y4W6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• spinocerebellar ataxia type 28 (Strong), mode of inheritance: AD
• spastic ataxia 5 (Strong), mode of inheritance: AR
• spinocerebellar ataxia type 28 (Supportive), mode of inheritance: AD
• spastic ataxia 5 (Supportive), mode of inheritance: AR
• spinocerebellar ataxia type 28 (Definitive), mode of inheritance: AD
• optic atrophy 12 (Strong), mode of inheritance: AD
• spastic ataxia 5 (Limited), mode of inheritance: AR
• spinocerebellar ataxia type 28 (Strong), mode of inheritance: AD
• spastic ataxia 5 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Optic atrophy 12; Spinocerebellar ataxia 28; Spastic ataxia 5, autosomal recessive	AD/AR	General	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	Neurologic; Ophthalmologic	16251216; 20725928; 20208537; 25401298; 32219868

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the AFG3L2 gene.

• not provided (294 variants)
• Spinocerebellar ataxia type 28 (74 variants)
• not specified (48 variants)
• Inborn genetic diseases (22 variants)
• Spastic ataxia 5 (19 variants)
• Optic atrophy 12 (9 variants)
• Autosomal dominant cerebellar ataxia (4 variants)
• Spastic ataxia (2 variants)
• Spinocerebellar ataxia type 28;Spastic ataxia 5;Optic atrophy 12 (2 variants)
• Spinocerebellar ataxia type 28;Spastic ataxia 5 (1 variants)
• Dystonic disorder;Abnormal cerebellum morphology;Optic atrophy;Hyperkinetic movements (1 variants)
• Spinocerebellar ataxia type 28;Optic atrophy 12;Spastic ataxia 5 (1 variants)
• - (1 variants)
• Optic atrophy 12;Spinocerebellar ataxia type 28;Spastic ataxia 5 (1 variants)
• Optic atrophy (1 variants)
• AFG3L2-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the AFG3L2 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			7	41	6	54
missense	6	16	128	6		156
nonsense	2	5				7
start loss						0
frameshift	4					4
inframe indel		1	2			3
splice donor/acceptor (+/-2bp)	1	1	2			4
splice region			7	10	3	20
non coding			12	48	37	97
Total	13	23	151	95	43

Highest pathogenic variant AF is 0.0000921

Variants in AFG3L2

This is a list of pathogenic ClinVar variants found in the AFG3L2 region.

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

Position	Type	Phenotype	Significance	ClinVar
18-12328980-T-G		Spinocerebellar ataxia type 28	Uncertain significance (Jan 13, 2018)
18-12329081-T-C		Spinocerebellar ataxia type 28	Uncertain significance (Jan 12, 2018)
18-12329186-A-T		Spinocerebellar ataxia type 28	Uncertain significance (Jan 12, 2018)
18-12329192-C-T		Spinocerebellar ataxia type 28	Uncertain significance (Jan 13, 2018)
18-12329239-C-T		Spinocerebellar ataxia type 28	Uncertain significance (Jan 13, 2018)
18-12329254-G-A		Spinocerebellar ataxia type 28	Benign (Jan 12, 2018)
18-12329344-T-C		Spinocerebellar ataxia type 28	Uncertain significance (Jan 12, 2018)
18-12329456-T-G		Spinocerebellar ataxia type 28	Benign/Likely benign (Dec 17, 2018)
18-12329537-C-G		Spinocerebellar ataxia type 28 • Optic atrophy 12 • Spastic ataxia 5	Benign (Jul 14, 2021)
18-12329549-G-A		not specified	Likely benign (Mar 24, 2016)
18-12329563-C-T		not specified • Spinocerebellar ataxia type 28 • AFG3L2-related disorder	Benign (Jan 03, 2020)
18-12329565-C-G		Spastic ataxia 5	Uncertain significance (Jun 05, 2023)
18-12329567-A-G			Uncertain significance (Sep 22, 2017)
18-12329577-T-C			Likely benign (May 11, 2018)
18-12329583-A-AC		-	no classification for the single variant (-)
18-12329584-C-G		not specified	Uncertain significance (Feb 28, 2024)
18-12329587-G-A		not specified	Uncertain significance (Sep 13, 2023)
18-12329595-C-T			Likely benign (Apr 12, 2023)
18-12329600-T-C		Inborn genetic diseases	Uncertain significance (Oct 25, 2022)
18-12329601-C-T			Benign (Jan 06, 2023)
18-12329609-C-T			Uncertain significance (Aug 13, 2021)
18-12329611-C-T			Uncertain significance (Jun 24, 2014)
18-12329612-G-A		Spinocerebellar ataxia type 28	Uncertain significance (Jan 01, 2024)
18-12329613-C-A		Spinocerebellar ataxia type 28	Uncertain significance (Jan 13, 2018)
18-12329632-A-G			Uncertain significance (Jul 25, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
AFG3L2	protein_coding	protein_coding	ENST00000269143	17	48371

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
5.25e-9	1.00	125683	0	65	125748	0.000258

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.99	303	417	0.726	0.0000242	5171
Missense in Polyphen		66	151.11	0.43678		1870
Synonymous	-0.639	165	155	1.07	0.00000971	1570
Loss of Function	3.13	21	43.2	0.486	0.00000279	496

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000377	0.000377
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000109	0.000109
Finnish	0.0000932	0.0000924
European (Non-Finnish)	0.000343	0.000334
Middle Eastern	0.000109	0.000109
South Asian	0.000229	0.000229
Other	0.000331	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: ATP-dependent protease which is essential for axonal and neuron development. In neurons, mediates degradation of SMDT1/EMRE before its assembly with the uniporter complex, limiting the availability of SMDT1/EMRE for MCU assembly and promoting efficient assembly of gatekeeper subunits with MCU (PubMed:27642048). Required for the maturation of paraplegin (SPG7) after its cleavage by mitochondrial-processing peptidase (MPP), converting it into a proteolytically active mature form (By similarity). {ECO:0000250|UniProtKB:Q8JZQ2, ECO:0000269|PubMed:27642048}.
• Disease: DISEASE: Spinocerebellar ataxia 28 (SCA28) [MIM:610246]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA28 is an autosomal dominant cerebellar ataxia (ADCA) with a slow progressive course and no evidence of sensory involvement or cognitive impairment. {ECO:0000269|PubMed:20208537, ECO:0000269|PubMed:20354562, ECO:0000269|PubMed:20725928, ECO:0000269|PubMed:24293060, ECO:0000269|PubMed:26677414, ECO:0000269|PubMed:29053796}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spastic ataxia 5, autosomal recessive (SPAX5) [MIM:614487]: A neurodegenerative disorder characterized by early onset spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. {ECO:0000269|PubMed:22022284}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Transport of small molecules;Mitochondrial calcium ion transport;Processing of SMDT1 (Consensus)

Recessive Scores

• pRec: 0.110

Intolerance Scores

• loftool: 0.201
• rvis_EVS: -0.6
• rvis_percentile_EVS: 17.91

Haploinsufficiency Scores

• pHI: 0.530
• hipred: Y
• hipred_score: 0.625
• ghis: 0.593

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.976

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Afg3l2
• Phenotype: adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); 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); growth/size/body region phenotype; cellular 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); muscle phenotype; pigmentation 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); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; immune system phenotype

Gene ontology

• Biological process: proteolysis;mitochondrial calcium ion transmembrane transport;axonogenesis;neuromuscular junction development;mitochondrial fusion;protein processing;protein autoprocessing;nerve development;mitochondrial protein processing;calcium import into the mitochondrion;regulation of multicellular organism growth;cristae formation;myelination;muscle fiber development;mitochondrial calcium ion homeostasis;righting reflex
• Cellular component: mitochondrion;mitochondrial inner membrane;m-AAA complex
• Molecular function: metalloendopeptidase activity;protein binding;ATP binding;metallopeptidase activity;zinc ion binding;unfolded protein binding