PPA2

inorganic pyrophosphatase 2

Basic information

Region (hg38): 4:105369077-105474067

Links

ENSG00000138777 ∙ NCBI:27068 ∙ OMIM:609988 ∙ HGNC:28883 ∙ Uniprot:Q9H2U2 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• sudden cardiac failure, infantile (Strong), mode of inheritance: AR
• sudden cardiac failure, infantile (Definitive), mode of inheritance: AR
• sudden cardiac failure, infantile (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Sudden cardiac failure, alcohol induced	AR	General	Individuals have been reported as suffering sudden cardiac failure after ingesting small amounts of alcohol, and awareness may allow avoidance of triggering agents as well as early diagnosis allowing preventive measures (eg, ICD)	Cardiovascular	27523597; 27523598

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PPA2 gene.

• not_provided (301 variants)
• Inborn_genetic_diseases (40 variants)
• Sudden_cardiac_failure,_infantile (24 variants)
• Sudden_cardiac_failure,_alcohol-induced (16 variants)
• not_specified (7 variants)
• PPA2-related_disorder (6 variants)
• Cardiovascular_phenotype (2 variants)
• sudden_cardiac_failure (1 variants)
• mitochondrial_cardiomyopathy_and_sudden_cardiac_failure (1 variants)
• Cardiomyopathy,_mitochondrial (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PPA2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000176869.3. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				63	2	65
missense	3	15	110	10		138
nonsense	2	2	4			8
start loss						0
frameshift			6			6
splice donor/acceptor (+/-2bp)		2	3			5
Total	5	19	123	73	2

Highest pathogenic variant AF is 0.0010266774

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PPA2	protein_coding	protein_coding	ENST00000341695	12	105005

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.18e-10	0.178	125717	0	31	125748	0.000123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.435	159	175	0.908	0.00000865	2184
Missense in Polyphen		61	75.552	0.80739		945
Synonymous	0.318	57	60.1	0.948	0.00000293	588
Loss of Function	0.621	17	20.0	0.850	9.36e-7	255

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000259	0.000247
Ashkenazi Jewish	0.00	0.00
East Asian	0.000166	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.000166	0.000149
Middle Eastern	0.000166	0.000163
South Asian	0.000184	0.000163
Other	0.000164	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Hydrolyzes inorganic pyrophosphate (PubMed:27523597). This activity is essential for correct regulation of mitochondrial membrane potential, and mitochondrial organization and function (PubMed:27523598). {ECO:0000269|PubMed:27523597, ECO:0000269|PubMed:27523598}.
• Disease: DISEASE: Sudden cardiac failure, infantile (SCFI) [MIM:617222]: A disease characterized by sudden death within the first 2 years of life due to unexpected cardiac arrest. Some patients manifest hypertrophic cardiomyopathy, lipid accumulation in myocardium, degeneration of mitochondrial cristae, metabolic acidosis, and elevated plasma lactate levels. SCFI transmission pattern is consistent with autosomal recessive inheritance. {ECO:0000269|PubMed:27523597, ECO:0000269|PubMed:27523598}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Oxidative phosphorylation - Homo sapiens (human);tRNA Aminoacylation;Translation;Metabolism of proteins;Pyrophosphate hydrolysis;Metabolism;Mitochondrial tRNA aminoacylation (Consensus)

Recessive Scores

• pRec: 0.145

Intolerance Scores

• loftool: 0.940
• rvis_EVS: 0
• rvis_percentile_EVS: 53.73

Haploinsufficiency Scores

• pHI: 0.0435
• hipred: N
• hipred_score: 0.177
• ghis: 0.605

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.597

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ppa2

Gene ontology

• Biological process: tRNA aminoacylation for protein translation;protein dephosphorylation;phosphate-containing compound metabolic process;regulation of mitochondrial membrane potential;diphosphate metabolic process
• Cellular component: mitochondrial matrix
• Molecular function: magnesium ion binding;inorganic diphosphatase activity;protein serine/threonine phosphatase activity