PKP2

plakophilin 2, the group of Plakophilins|Armadillo repeat containing

Basic information

Region (hg38): 12:32790745-32896798

Links

ENSG00000057294 ∙ NCBI:5318 ∙ OMIM:602861 ∙ HGNC:9024 ∙ Uniprot:Q99959 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Brugada syndrome (Limited), mode of inheritance: AD
• left ventricular noncompaction (Supportive), mode of inheritance: AD
• arrhythmogenic right ventricular dysplasia 9 (Strong), mode of inheritance: AD
• arrhythmogenic right ventricular dysplasia 9 (Definitive), mode of inheritance: AD
• Brugada syndrome 1 (Disputed Evidence), mode of inheritance: AD
• catecholaminergic polymorphic ventricular tachycardia (Disputed Evidence), mode of inheritance: AD
• dilated cardiomyopathy (Disputed Evidence), mode of inheritance: AD
• arrhythmogenic right ventricular cardiomyopathy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Arrhythmogenic right ventricular dysplasia, familial 9	AD	Cardiovascular	Due to risk of severe sequelae including sudden cardiac death, individuals require ICD placement regardless of classic risk factors related to ICD necessity in clinically similar patients without PKP2 variants	Cardiovascular	15489853; 16549640; 20301310

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PKP2 gene.

• Arrhythmogenic_right_ventricular_dysplasia_9 (1388 variants)
• Cardiomyopathy (735 variants)
• Arrhythmogenic_right_ventricular_cardiomyopathy (715 variants)
• Cardiovascular_phenotype (713 variants)
• not_provided (447 variants)
• not_specified (216 variants)
• PKP2-related_disorder (41 variants)
• Familial_isolated_arrhythmogenic_right_ventricular_dysplasia (29 variants)
• Primary_dilated_cardiomyopathy (7 variants)
• Primary_familial_hypertrophic_cardiomyopathy (5 variants)
• Hypertrophic_cardiomyopathy (5 variants)
• Ventricular_tachycardia (5 variants)
• Sudden_unexplained_death (3 variants)
• Long_QT_syndrome (3 variants)
• Cardiac_arrhythmia (3 variants)
• Left_ventricular_noncompaction_cardiomyopathy (2 variants)
• Left_ventricular_noncompaction (2 variants)
• Brugada_syndrome (2 variants)
• Arrhythmogenic_ventricular_cardiomyopathy (2 variants)
• Dilated_cardiomyopathy_1A (1 variants)
• Premature_ventricular_contraction (1 variants)
• Dilated_cardiomyopathy_3B (1 variants)
• AV_junctional_rhythm (1 variants)
• Amyloidosis,_hereditary_systemic_1 (1 variants)
• Left_ventricular_noncompaction_1 (1 variants)
• Sudden_cardiac_death (1 variants)
• Dilated_cardiomyopathy_1S (1 variants)
• Ventricular_fibrillation,_paroxysmal_familial,_type_1 (1 variants)
• Family_history_of_cardiomyopathy (1 variants)
• Primary_familial_dilated_cardiomyopathy (1 variants)
• Conduction_disorder_of_the_heart (1 variants)
• Long_QT_syndrome_1 (1 variants)
• Becker_muscular_dystrophy (1 variants)
• Arrhythmogenic_cardiomyopathy (1 variants)
• Ventricular_fibrillation (1 variants)
• Duchenne_muscular_dystrophy (1 variants)
• Arrhythmogenic_right_ventricular_dysplasia_1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PKP2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_001005242.3. 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	1	4	10	361	10	386
missense	8	13	855	74	9	959
nonsense	65	19				84
start loss	1	3	1			5
frameshift	108	78	4			190
splice donor/acceptor (+/-2bp)	18	35	1	1		55
Total	201	152	871	436	19

Highest pathogenic variant AF is 0.000076840515

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PKP2	protein_coding	protein_coding	ENST00000070846	14	106096

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.11e-18	0.117	125638	0	110	125748	0.000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.213	513	500	1.03	0.0000303	5724
Missense in Polyphen		130	135.54	0.95909		1684
Synonymous	0.216	208	212	0.981	0.0000142	1778
Loss of Function	1.25	32	40.6	0.788	0.00000233	439

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00282	0.00266
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.000326	0.000326
Finnish	0.0000928	0.0000924
European (Non-Finnish)	0.000406	0.000360
Middle Eastern	0.000326	0.000326
South Asian	0.000359	0.000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May play a role in junctional plaques. {ECO:0000269|PubMed:22781308}.
• Pathway: Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human);Arrhythmogenic Right Ventricular Cardiomyopathy;EMT transition in Colorectal Cancer;Keratinization;Developmental Biology;EGFR1;Formation of the cornified envelope (Consensus)

Recessive Scores

• pRec: 0.123

Intolerance Scores

• loftool: 0.399
• rvis_EVS: 0.65
• rvis_percentile_EVS: 84.18

Haploinsufficiency Scores

• pHI: 0.680
• hipred: N
• hipred_score: 0.435
• ghis: 0.408

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.732

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pkp2
• 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); cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype

Zebrafish Information Network

• Gene name: pkp2
• Affected structure: post-vent region
• Phenotype tag: abnormal
• Phenotype quality: kinked

Gene ontology

• Biological process: desmosome assembly;cell-cell junction assembly;heart development;positive regulation of sodium ion transport;keratinization;adherens junction maintenance;intermediate filament bundle assembly;maintenance of animal organ identity;ventricular cardiac muscle tissue morphogenesis;cornification;protein localization to plasma membrane;cardiac muscle cell action potential involved in contraction;ventricular cardiac muscle cell action potential;cell-cell signaling involved in cardiac conduction;cell communication by electrical coupling involved in cardiac conduction;bundle of His cell-Purkinje myocyte adhesion involved in cell communication;regulation of heart rate by cardiac conduction;cell-cell adhesion;regulation of ventricular cardiac muscle cell action potential
• Cellular component: cornified envelope;nucleus;nucleoplasm;cytoplasm;intermediate filament;plasma membrane;cell-cell junction;adherens junction;cell-cell adherens junction;intercalated disc;integral component of membrane;cell junction;desmosome;messenger ribonucleoprotein complex
• Molecular function: protein kinase C binding;protein binding;sodium channel regulator activity;intermediate filament binding;protein-containing complex scaffold activity;ion channel binding;alpha-catenin binding;cadherin binding;cell adhesive protein binding involved in bundle of His cell-Purkinje myocyte communication