PLA2G6

phospholipase A2 group VI, the group of Phospholipases|Ankyrin repeat domain containing|Patatin like phospholipase domain containing

Basic information

Region (hg38): 22:38111494-38214778

Links

ENSG00000184381 ∙ NCBI:8398 ∙ OMIM:603604 ∙ HGNC:9039 ∙ Uniprot:O60733 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neurodegeneration with brain iron accumulation 2A (Strong), mode of inheritance: AR
• neurodegeneration with brain iron accumulation 2B (Strong), mode of inheritance: AR
• autosomal recessive Parkinson disease 14 (Strong), mode of inheritance: AR
• neurodegeneration with brain iron accumulation 2A (Definitive), mode of inheritance: AR
• neurodegeneration with brain iron accumulation 2B (Definitive), mode of inheritance: AR
• autosomal recessive Parkinson disease 14 (Moderate), mode of inheritance: AR
• neurodegeneration with brain iron accumulation 2A (Supportive), mode of inheritance: AR
• autosomal recessive Parkinson disease 14 (Supportive), mode of inheritance: AR
• neurodegeneration with brain iron accumulation 2A (Definitive), mode of inheritance: AR
• neurodegeneration with brain iron accumulation 2A (Strong), mode of inheritance: AR
• neurodegeneration with brain iron accumulation 2B (Strong), mode of inheritance: AR
• autosomal recessive Parkinson disease 14 (Strong), mode of inheritance: AR
• PLA2G6-associated neurodegeneration (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Parkinson disease 14, autosomal recessive	AR	Neurologic	In Parkinson disease 14, response to levodopa has been documented	Neurologic	17033970; 16783378; 18443314; 18981035; 18570303; 20584031; 20886109; 20938027; 21520282; 21700586; 21812034; 22934738
Some individuals with Neurodegeneration with brain iron accumulation have been described as having Karak syndrome

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PLA2G6 gene.

• Infantile neuroaxonal dystrophy (583 variants)
• not provided (294 variants)
• PLA2G6-associated neurodegeneration (153 variants)
• Iron accumulation in brain (53 variants)
• not specified (44 variants)
• Inborn genetic diseases (43 variants)
• Neurodegeneration with brain iron accumulation 2B (26 variants)
• Neurodegeneration with brain iron accumulation (17 variants)
• Autosomal recessive Parkinson disease 14;Infantile neuroaxonal dystrophy;Neurodegeneration with brain iron accumulation 2B (17 variants)
• Autosomal recessive Parkinson disease 14 (10 variants)
• Infantile neuroaxonal dystrophy;Neurodegeneration with brain iron accumulation 2B;Autosomal recessive Parkinson disease 14 (10 variants)
• Abnormality of the nervous system (5 variants)
• PLA2G6-related condition (4 variants)
• Autosomal recessive Parkinson disease 14;Neurodegeneration with brain iron accumulation 2B;Infantile neuroaxonal dystrophy (4 variants)
• Infantile neuroaxonal dystrophy;Autosomal recessive Parkinson disease 14;Neurodegeneration with brain iron accumulation 2B (3 variants)
• Infantile neuroaxonal dystrophy;Neurodegeneration with brain iron accumulation 2B (3 variants)
• Abnormal brain morphology (2 variants)
• See cases (2 variants)
• Global developmental delay;Congenital cerebellar hypoplasia;Microcephaly;Cerebellar ataxia;Developmental regression (1 variants)
• Spastic ataxia (1 variants)
• Infantile osteopetrosis with neuroaxonal dysplasia (1 variants)
• Neurodegeneration with brain iron accumulation 2B;Autosomal recessive Parkinson disease 14;Infantile neuroaxonal dystrophy (1 variants)
• Autism;Seizure (1 variants)
• Karak syndrome (1 variants)
• - (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PLA2G6 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			3	135	4	142
missense	11	44	249	2	2	308
nonsense	13	5	1			19
start loss	2					2
frameshift	19	12	1			32
inframe indel	1		2			3
splice donor/acceptor (+/-2bp)	7	11				18
splice region	2		14	16		32
non coding	1		22	102	49	174
Total	54	72	278	239	55

Highest pathogenic variant AF is 0.0000263

Variants in PLA2G6

This is a list of pathogenic ClinVar variants found in the PLA2G6 region.

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

Position	Type	Phenotype	Significance	ClinVar
22-38111541-C-T		PLA2G6-associated neurodegeneration	Uncertain significance (Jan 13, 2018)
22-38111572-G-C		PLA2G6-associated neurodegeneration	Likely benign (Jan 12, 2018)
22-38111596-G-C		PLA2G6-associated neurodegeneration	Uncertain significance (Jan 13, 2018)
22-38111613-G-C		PLA2G6-associated neurodegeneration	Uncertain significance (Jan 12, 2018)
22-38111620-G-A		PLA2G6-associated neurodegeneration	Uncertain significance (Jan 13, 2018)
22-38111646-G-A		PLA2G6-associated neurodegeneration	Uncertain significance (Apr 27, 2017)
22-38111668-G-C		PLA2G6-associated neurodegeneration	Uncertain significance (Jan 12, 2018)
22-38111688-G-A		PLA2G6-associated neurodegeneration	Uncertain significance (Jan 12, 2018)
22-38111811-G-T		PLA2G6-associated neurodegeneration	Benign (Jan 13, 2018)
22-38111860-C-T		PLA2G6-associated neurodegeneration	Benign (Jan 12, 2018)
22-38111931-G-C			Likely benign (Oct 17, 2018)
22-38111970-G-A		PLA2G6-associated neurodegeneration	Uncertain significance (Jan 13, 2018)
22-38111973-AGGCGG-A		Infantile neuroaxonal dystrophy	Benign/Likely benign (Aug 20, 2018)
22-38112001-A-G		PLA2G6-associated neurodegeneration	Uncertain significance (Jan 13, 2018)
22-38112013-G-A			Likely benign (Oct 17, 2018)
22-38112080-C-A			Likely benign (Oct 17, 2018)
22-38112126-G-A		PLA2G6-associated neurodegeneration	Uncertain significance (Jan 13, 2018)
22-38112142-G-A		not specified	Uncertain significance (Feb 08, 2013)
22-38112164-G-C		Infantile neuroaxonal dystrophy	Likely benign (Nov 28, 2022)
22-38112165-G-C		not specified • Infantile neuroaxonal dystrophy • PLA2G6-associated neurodegeneration • Autosomal recessive Parkinson disease 14	Conflicting classifications of pathogenicity (Jan 31, 2024)
22-38112166-G-A			Uncertain significance (Jun 10, 2022)
22-38112170-G-A		Infantile neuroaxonal dystrophy	Likely benign (Jan 14, 2023)
22-38112172-G-A			Uncertain significance (Jul 10, 2019)
22-38112186-A-T		Iron accumulation in brain	Likely pathogenic (Jul 09, 2013)
22-38112191-C-T		Infantile neuroaxonal dystrophy	Likely benign (Sep 05, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PLA2G6	protein_coding	protein_coding	ENST00000332509	16	94196

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.48e-10	0.971	125684	0	63	125747	0.000251

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.21	425	502	0.847	0.0000350	5244
Missense in Polyphen		134	170.61	0.78542		1755
Synonymous	1.83	181	215	0.841	0.0000158	1639
Loss of Function	2.20	21	35.1	0.598	0.00000201	379

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000639	0.000638
Ashkenazi Jewish	0.00	0.00
East Asian	0.000381	0.000381
Finnish	0.0000932	0.0000924
European (Non-Finnish)	0.000294	0.000290
Middle Eastern	0.000381	0.000381
South Asian	0.000163	0.000163
Other	0.000491	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the release of fatty acids from phospholipids. It has been implicated in normal phospholipid remodeling, nitric oxide-induced or vasopressin-induced arachidonic acid release and in leukotriene and prostaglandin production. May participate in fas mediated apoptosis and in regulating transmembrane ion flux in glucose-stimulated B-cells. Has a role in cardiolipin (CL) deacylation. Required for both speed and directionality of monocyte MCP1/CCL2-induced chemotaxis through regulation of F- actin polymerization at the pseudopods.
• Disease: DISEASE: Neurodegeneration with brain iron accumulation 2A (NBIA2A) [MIM:256600]: A neurodegenerative disease characterized by pathologic axonal swelling and spheroid bodies in the central nervous system. Onset is within the first 2 years of life with death by age 10 years. {ECO:0000269|PubMed:16783378, ECO:0000269|PubMed:17033970, ECO:0000269|PubMed:23749988}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Parkinson disease 14 (PARK14) [MIM:612953]: An adult- onset progressive neurodegenerative disorder characterized by parkinsonism, dystonia, severe cognitive decline, cerebral and cerebellar atrophy and absent iron in the basal ganglia on magnetic resonance imaging. {ECO:0000269|PubMed:18570303}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Inflammatory mediator regulation of TRP channels - Homo sapiens (human);Fc gamma R-mediated phagocytosis - Homo sapiens (human);Ether lipid metabolism - Homo sapiens (human);Glycerophospholipid metabolism - Homo sapiens (human);Vascular smooth muscle contraction - Homo sapiens (human);alpha-Linolenic acid metabolism - Homo sapiens (human);Arachidonic acid metabolism - Homo sapiens (human);Linoleic acid metabolism - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);Eicosanoid Synthesis;Spinal Cord Injury;Ras Signaling;Vesicle-mediated transport;Membrane Trafficking;Metabolism of lipids;Metabolism;phospholipases;Acyl chain remodelling of PC;Acyl chain remodeling of CL;COPI-independent Golgi-to-ER retrograde traffic;Golgi-to-ER retrograde transport;Glycerophospholipid biosynthesis;Phospholipid metabolism;Acyl chain remodelling of PE;Intra-Golgi and retrograde Golgi-to-ER traffic (Consensus)

Recessive Scores

• pRec: 0.176

Intolerance Scores

• loftool: 0.843
• rvis_EVS: -1.59
• rvis_percentile_EVS: 3.08

Haploinsufficiency Scores

• pHI: 0.169
• hipred: N
• hipred_score: 0.254
• ghis: 0.571

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.853

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pla2g6
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); reproductive system phenotype; hematopoietic system phenotype; vision/eye 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); skeleton phenotype; cellular phenotype; immune system phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype; muscle phenotype

Gene ontology

• Biological process: positive regulation of protein phosphorylation;chemotaxis;positive regulation of cytosolic calcium ion concentration;memory;urinary bladder smooth muscle contraction;lipid catabolic process;antibacterial humoral response;cardiolipin biosynthetic process;response to endoplasmic reticulum stress;positive regulation of insulin secretion involved in cellular response to glucose stimulus;phosphatidylcholine acyl-chain remodeling;phosphatidylethanolamine acyl-chain remodeling;Fc-gamma receptor signaling pathway involved in phagocytosis;positive regulation of exocytosis;negative regulation of synaptic transmission, glutamatergic;maternal process involved in female pregnancy;positive regulation of protein kinase C signaling;positive regulation of release of cytochrome c from mitochondria;positive regulation of arachidonic acid secretion;positive regulation of blood vessel diameter;regulation of store-operated calcium channel activity;positive regulation of ceramide biosynthetic process
• Cellular component: extracellular space;mitochondrion;microtubule organizing center;cytosol;membrane
• Molecular function: phospholipase A2 activity;calmodulin binding;hydrolase activity;serine hydrolase activity;protein kinase binding;ATP-dependent protein binding;calcium-independent phospholipase A2 activity;phospholipase A2 activity (consuming 1,2-dipalmitoylphosphatidylcholine);phospholipase A2 activity consuming 1,2-dioleoylphosphatidylethanolamine)