PNPLA2

patatin like phospholipase domain containing 2, the group of Patatin like phospholipase domain containing|Lipases

Basic information

Region (hg38): 11:818914-825573

Links

ENSG00000177666 ∙ NCBI:57104 ∙ OMIM:609059 ∙ HGNC:30802 ∙ Uniprot:Q96AD5 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neutral lipid storage myopathy (Supportive), mode of inheritance: AR
• neutral lipid storage myopathy (Strong), mode of inheritance: AR
• neutral lipid storage myopathy (Definitive), mode of inheritance: AR
• neutral lipid storage myopathy (Strong), mode of inheritance: AR
• neutral lipid storage myopathy (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neutral lipid storage disease with myopathy	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	Dermatologic; Cardiovascular; Endocrine; Gastrointestinal; Musculoskeletal	17187067; 22832386

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PNPLA2 gene.

• Neutral lipid storage myopathy (14 variants)
• not provided (2 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PNPLA2 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			5	128	5	138
missense	2	3	226	6	4	241
nonsense	2					2
start loss						0
frameshift	10	1	5			16
inframe indel			7			7
splice donor/acceptor (+/-2bp)	1	3				4
splice region			8	15		23
non coding			27	60	12	99
Total	15	7	270	194	21

Highest pathogenic variant AF is 0.0000264

Variants in PNPLA2

This is a list of pathogenic ClinVar variants found in the PNPLA2 region.

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

Position	Type	Phenotype	Significance	ClinVar
11-818937-G-T		Neutral lipid storage myopathy	Uncertain significance (Jan 13, 2018)
11-818939-A-G		Neutral lipid storage myopathy	Uncertain significance (Jan 13, 2018)
11-818945-A-G		Neutral lipid storage myopathy	Uncertain significance (Jan 13, 2018)
11-819464-T-G			Benign (Jun 28, 2018)
11-819486-T-C			Benign (Jun 19, 2018)
11-819526-G-A			Likely benign (May 25, 2021)
11-819563-C-T		Neutral lipid storage myopathy	Uncertain significance (Jan 13, 2018)
11-819599-C-T		Neutral lipid storage myopathy	Uncertain significance (Jan 13, 2018)
11-819601-C-T		Neutral lipid storage myopathy	Uncertain significance (Jan 13, 2018)
11-819602-G-A		Neutral lipid storage myopathy	Uncertain significance (Jan 12, 2018)
11-819636-G-A		Neutral lipid storage myopathy	Uncertain significance (Jan 13, 2018)
11-819688-C-T		Neutral lipid storage myopathy	Uncertain significance (Jan 13, 2018)
11-819700-C-A		Neutral lipid storage myopathy	Likely benign (Jan 13, 2018)
11-819728-C-T		Neutral lipid storage myopathy	Uncertain significance (Mar 08, 2022)
11-819729-G-A		Neutral lipid storage myopathy	Uncertain significance (Dec 11, 2019)
11-819736-G-A		Neutral lipid storage myopathy	Likely benign (Mar 29, 2023)
11-819739-G-A		Neutral lipid storage myopathy	Likely benign (Aug 02, 2021)
11-819742-G-A		Neutral lipid storage myopathy	Likely pathogenic (Jun 01, 2022)
11-819748-C-T		Neutral lipid storage myopathy	Likely benign (May 01, 2024)
11-819750-C-T		Neutral lipid storage myopathy • Abnormality of the musculature	Likely pathogenic (Jul 10, 2021)
11-819751-G-C		Neutral lipid storage myopathy	Likely benign (Jan 17, 2022)
11-819754-C-T		Neutral lipid storage myopathy	Conflicting classifications of pathogenicity (Dec 13, 2023)
11-819758-G-A		Neutral lipid storage myopathy	Uncertain significance (Sep 01, 2021)
11-819760-C-T			Likely benign (Feb 16, 2018)
11-819761-T-A		Neutral lipid storage myopathy	Uncertain significance (May 29, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PNPLA2	protein_coding	protein_coding	ENST00000336615	9	6672

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00411	0.989	125720	0	22	125742	0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.00894	308	308	1.00	0.0000216	3119
Missense in Polyphen		87	97.892	0.88873		1026
Synonymous	-0.548	156	148	1.06	0.0000112	1061
Loss of Function	2.36	7	17.8	0.394	8.52e-7	205

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000117	0.000117
Ashkenazi Jewish	0.00	0.00
East Asian	0.000275	0.000272
Finnish	0.000145	0.000139
European (Non-Finnish)	0.0000755	0.0000703
Middle Eastern	0.000275	0.000272
South Asian	0.0000662	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the initial step in triglyceride hydrolysis in adipocyte and non-adipocyte lipid droplets (PubMed:15550674). Also has acylglycerol transacylase activity. May act coordinately with LIPE/HLS within the lipolytic cascade. Regulates adiposome size and may be involved in the degradation of adiposomes (PubMed:16239926). May play an important role in energy homeostasis. May play a role in the response of the organism to starvation, enhancing hydrolysis of triglycerides and providing free fatty acids to other tissues to be oxidized in situations of energy depletion. {ECO:0000269|PubMed:15364929, ECO:0000269|PubMed:15550674, ECO:0000269|PubMed:16239926}.
• Disease: DISEASE: Note=Genetic variations in PNPLA2 may be associated with risk of diabetes mellitus type 2. {ECO:0000269|PubMed:16644682}.; DISEASE: Neutral lipid storage disease with myopathy (NLSDM) [MIM:610717]: Neutral lipid storage disorder (NLSD) with myopathy but without ichthyosis. NLSDs are characterized by the presence of triglyceride-containing cytoplasmic droplets in leukocytes and in other tissues, including bone marrow, skin, and muscle. Individuals with NLSDM did not show obesity, in spite of a defect in triglyceride degradation in fibroblasts and in marked triglyceride storage in liver, muscles, and other visceral cells. {ECO:0000269|PubMed:17187067}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Regulation of lipolysis in adipocytes - Homo sapiens (human);Glycerolipid metabolism - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Fatty Acid Beta Oxidation;Lipid storage and perilipins in skeletal muscle;Triacylglyceride Synthesis;Lipid Metabolism Pathway;Liver steatosis AOP;Post-translational protein phosphorylation;Metabolism of lipids;Post-translational protein modification;Metabolism of proteins;Acyl chain remodeling of DAG and TAG;Metabolism;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);triacylglycerol degradation;Glycerophospholipid biosynthesis;Phospholipid metabolism (Consensus)

Recessive Scores

• pRec: 0.217

Intolerance Scores

• loftool: 0.568
• rvis_EVS: 0.04
• rvis_percentile_EVS: 57.31

Haploinsufficiency Scores

• pHI: 0.400
• hipred: N
• hipred_score: 0.265
• ghis: 0.463

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.691

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pnpla2
• 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); 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); respiratory system phenotype; liver/biliary system phenotype; growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype

Gene ontology

• Biological process: negative regulation of sequestering of triglyceride;positive regulation of triglyceride catabolic process;triglyceride catabolic process;lipid storage;lipid droplet organization;acylglycerol acyl-chain remodeling;post-translational protein modification;cellular protein metabolic process;lipid homeostasis
• Cellular component: nucleoplasm;cytoplasm;endoplasmic reticulum lumen;endoplasmic reticulum membrane;lipid droplet;cytosol;plasma membrane;membrane;integral component of membrane
• Molecular function: lipoprotein lipase activity;triglyceride lipase activity;acylglycerol O-acyltransferase activity