PRKD1

protein kinase D1, the group of Pleckstrin homology domain containing

Basic information

Region (hg38): 14:29576479-30191898

Previous symbols: [ "PRKCM" ]

Links

ENSG00000184304 ∙ NCBI:5587 ∙ OMIM:605435 ∙ HGNC:9407 ∙ Uniprot:Q15139 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• congenital heart defects and ectodermal dysplasia (Limited), mode of inheritance: AD
• congenital heart defects and ectodermal dysplasia (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Congenital heart defects and ectodermal dysplasia	AD	Cardiovascular	The condition can involve congenital cardiac anomalies, and awareness may allow early management	Cardiovascular; Dermatologic; Neurologic	27479907

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PRKD1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PRKD1 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			1	17	5	23
missense		2	79	12	3	96
nonsense			2			2
start loss						0
frameshift						0
inframe indel			1		1	2
splice donor/acceptor (+/-2bp)		2				2
splice region				5	2	7
non coding			1	1	4	6
Total	0	4	84	30	13

Variants in PRKD1

This is a list of pathogenic ClinVar variants found in the PRKD1 region.

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

Position	Type	Phenotype	Significance	ClinVar
14-29577254-C-T			Likely benign (Jul 11, 2018)
14-29577259-A-C			Benign/Likely benign (Jul 01, 2022)
14-29577305-T-C			Benign (Aug 01, 2023)
14-29577305-TG-T		PRKD1-related disorder	Uncertain significance (May 17, 2024)
14-29577320-T-C		PRKD1-related disorder	Benign (Dec 31, 2019)
14-29577351-G-A		Congenital heart defects and ectodermal dysplasia	Uncertain significance (Apr 03, 2020)
14-29577354-C-T		not specified	Uncertain significance (Sep 14, 2022)
14-29577358-T-C		PRKD1-related disorder	Likely benign (Sep 09, 2019)
14-29577404-C-T		not specified	Uncertain significance (Aug 30, 2021)
14-29577412-G-A			Likely benign (Dec 31, 2019)
14-29577413-A-T		PRKD1-related disorder	Likely benign (Jun 19, 2019)
14-29577455-T-A		not specified	Uncertain significance (Feb 13, 2024)
14-29578297-G-T			Uncertain significance (Jan 30, 2023)
14-29578338-C-T			Benign (Jul 05, 2018)
14-29578342-T-C		not specified	Uncertain significance (Nov 29, 2021)
14-29578352-G-C		not specified	Uncertain significance (May 04, 2022)
14-29578374-C-T		Congenital heart defects and ectodermal dysplasia	Benign (Oct 25, 2021)
14-29597503-T-C		PRKD1-related disorder	Benign/Likely benign (Dec 31, 2019)
14-29597555-G-A		PRKD1-related disorder	Likely benign (Jun 11, 2019)
14-29597590-C-T			Likely benign (May 18, 2018)
14-29597634-A-C		not specified	Uncertain significance (Jan 04, 2024)
14-29597641-G-A		not specified	Uncertain significance (Oct 02, 2023)
14-29597645-G-A			Uncertain significance (Aug 01, 2017)
14-29597655-T-C		not specified	Uncertain significance (Dec 14, 2023)
14-29597706-C-T		Congenital heart defects and ectodermal dysplasia	Uncertain significance (Aug 12, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PRKD1	protein_coding	protein_coding	ENST00000331968	18	615418

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.65e-7	1.00	125688	0	59	125747	0.000235

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.43	411	501	0.820	0.0000274	6005
Missense in Polyphen		124	186.03	0.66656		2090
Synonymous	-0.522	193	184	1.05	0.0000107	1740
Loss of Function	3.52	18	42.9	0.420	0.00000217	519

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000898	0.000886
Ashkenazi Jewish	0.00	0.00
East Asian	0.000222	0.000217
Finnish	0.00	0.00
European (Non-Finnish)	0.000258	0.000255
Middle Eastern	0.000222	0.000217
South Asian	0.000229	0.000229
Other	0.000327	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and trafficking, cell survival through NF-kappa-B activation, cell migration, cell differentiation by mediating HDAC7 nuclear export, cell proliferation via MAPK1/3 (ERK1/2) signaling, and plays a role in cardiac hypertrophy, VEGFA-induced angiogenesis, genotoxic-induced apoptosis and flagellin-stimulated inflammatory response. Phosphorylates the epidermal growth factor receptor (EGFR) on dual threonine residues, which leads to the suppression of epidermal growth factor (EGF)-induced MAPK8/JNK1 activation and subsequent JUN phosphorylation. Phosphorylates RIN1, inducing RIN1 binding to 14-3-3 proteins YWHAB, YWHAE and YWHAZ and increased competition with RAF1 for binding to GTP-bound form of Ras proteins (NRAS, HRAS and KRAS). Acts downstream of the heterotrimeric G-protein beta/gamma-subunit complex to maintain the structural integrity of the Golgi membranes, and is required for protein transport along the secretory pathway. In the trans-Golgi network (TGN), regulates the fission of transport vesicles that are on their way to the plasma membrane. May act by activating the lipid kinase phosphatidylinositol 4-kinase beta (PI4KB) at the TGN for the local synthesis of phosphorylated inositol lipids, which induces a sequential production of DAG, phosphatidic acid (PA) and lyso-PA (LPA) that are necessary for membrane fission and generation of specific transport carriers to the cell surface. Under oxidative stress, is phosphorylated at Tyr-463 via SRC-ABL1 and contributes to cell survival by activating IKK complex and subsequent nuclear translocation and activation of NFKB1. Involved in cell migration by regulating integrin alpha-5/beta-3 recycling and promoting its recruitment in newly forming focal adhesion. In osteoblast differentiation, mediates the bone morphogenetic protein 2 (BMP2)- induced nuclear export of HDAC7, which results in the inhibition of HDAC7 transcriptional repression of RUNX2. In neurons, plays an important role in neuronal polarity by regulating the biogenesis of TGN-derived dendritic vesicles, and is involved in the maintenance of dendritic arborization and Golgi structure in hippocampal cells. May potentiate mitogenesis induced by the neuropeptide bombesin or vasopressin by mediating an increase in the duration of MAPK1/3 (ERK1/2) signaling, which leads to accumulation of immediate-early gene products including FOS that stimulate cell cycle progression. Plays an important role in the proliferative response induced by low calcium in keratinocytes, through sustained activation of MAPK1/3 (ERK1/2) pathway. Downstream of novel PKC signaling, plays a role in cardiac hypertrophy by phosphorylating HDAC5, which in turn triggers XPO1/CRM1-dependent nuclear export of HDAC5, MEF2A transcriptional activation and induction of downstream target genes that promote myocyte hypertrophy and pathological cardiac remodeling. Mediates cardiac troponin I (TNNI3) phosphorylation at the PKA sites, which results in reduced myofilament calcium sensitivity, and accelerated crossbridge cycling kinetics. The PRKD1-HDAC5 pathway is also involved in angiogenesis by mediating VEGFA-induced specific subset of gene expression, cell migration, and tube formation. In response to VEGFA, is necessary and required for HDAC7 phosphorylation which induces HDAC7 nuclear export and endothelial cell proliferation and migration. During apoptosis induced by cytarabine and other genotoxic agents, PRKD1 is cleaved by caspase-3 at Asp-378, resulting in activation of its kinase function and increased sensitivity of cells to the cytotoxic effects of genotoxic agents. In epithelial cells, is required for transducing flagellin-stimulated inflammatory responses by binding and phosphorylating TLR5, which contributes to MAPK14/p38 activation and production of inflammatory cytokines. May play a role in inflammatory response by mediating activation of NF-kappa- B. May be involved in pain transmission by directly modulating TRPV1 receptor. Plays a role in activated KRAS-mediated stabilization of ZNF304 in colorectal cancer (CRC) cells (PubMed:24623306). Regulates nuclear translocation of transcription factor TFEB in macrophages upon live S.enterica infection (By similarity). {ECO:0000250|UniProtKB:Q62101, ECO:0000269|PubMed:10523301, ECO:0000269|PubMed:10764790, ECO:0000269|PubMed:12505989, ECO:0000269|PubMed:12637538, ECO:0000269|PubMed:15471852, ECO:0000269|PubMed:17442957, ECO:0000269|PubMed:18332134, ECO:0000269|PubMed:18509061, ECO:0000269|PubMed:19135240, ECO:0000269|PubMed:19211839, ECO:0000269|PubMed:24623306}.
• Disease: DISEASE: Congenital heart defects and ectodermal dysplasia (CHDED) [MIM:617364]: An autosomal dominant syndrome characterized by atrial and/or ventricular septal congenital heart defects and variable features of ectodermal dysplasia, including sparse hair, dry skin, thin skin, fragile nails, premature loss of primary teeth, and small widely spaced teeth. Patients manifest developmental disabilities ranging from motor delay and delayed speech to global developmental retardation. {ECO:0000269|PubMed:27479907}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Aldosterone synthesis and secretion - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Proton Pump Inhibitor Pathway, Pharmacodynamics;Apoptosis Modulation and Signaling;miRs in Muscle Cell Differentiation;Cardiac Hypertrophic Response;Myometrial Relaxation and Contraction Pathways;G Protein Signaling Pathways;VEGFA-VEGFR2 Signaling Pathway;Wnt Signaling Pathway and Pluripotency;Calcium Regulation in the Cardiac Cell;Metabolism of lipids;TCR;Metabolism;BCR;EGFR1;Sphingolipid de novo biosynthesis;Sphingolipid metabolism;LPA receptor mediated events;IGF1 pathway (Consensus)

Recessive Scores

• pRec: 0.674

Intolerance Scores

• loftool: 0.295
• rvis_EVS: -0.95
• rvis_percentile_EVS: 9.32

Haploinsufficiency Scores

• pHI: 0.268
• hipred: Y
• hipred_score: 0.782
• ghis: 0.581

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.486

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Prkd1
• Phenotype: 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); 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); muscle phenotype

Zebrafish Information Network

• Gene name: prkd1
• Affected structure: lymphangioblast cord
• Phenotype tag: abnormal
• Phenotype quality: malformed

Gene ontology

• Biological process: angiogenesis;positive regulation of endothelial cell proliferation;protein phosphorylation;apoptotic process;inflammatory response;Golgi organization;signal transduction;integrin-mediated signaling pathway;Ras protein signal transduction;cell population proliferation;positive regulation of autophagy;positive regulation of endothelial cell migration;regulation of keratinocyte proliferation;positive regulation of neuron projection development;peptidyl-serine phosphorylation;peptidyl-threonine phosphorylation;sphingolipid biosynthetic process;regulation of protein stability;positive regulation of CREB transcription factor activity;positive regulation of peptidyl-serine phosphorylation;cellular response to amino acid starvation;cellular response to oxidative stress;intracellular signal transduction;cellular response to vascular endothelial growth factor stimulus;positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathway;positive regulation of I-kappaB kinase/NF-kappaB signaling;positive regulation of blood vessel endothelial cell migration;positive regulation of phosphatidylinositol 3-kinase activity;innate immune response;positive regulation of osteoblast differentiation;positive regulation of angiogenesis;negative regulation of endocytosis;positive regulation of transcription by RNA polymerase II;protein autophosphorylation;vascular endothelial growth factor receptor signaling pathway;Golgi vesicle transport;positive regulation of NF-kappaB transcription factor activity;negative regulation of cell death;cellular response to hydroperoxide;protein kinase D signaling;positive regulation of histone deacetylase activity;positive regulation of endothelial cell chemotaxis;regulation of integrin-mediated signaling pathway
• Cellular component: autophagosome membrane;Golgi apparatus;trans-Golgi network;cytosol;plasma membrane
• Molecular function: protein serine/threonine kinase activity;protein kinase C activity;protein binding;ATP binding;kinase activity;identical protein binding;metal ion binding