PCSK1

proprotein convertase subtilisin/kexin type 1, the group of Proprotein convertase subtilisin/kexin family

Basic information

Region (hg38): 5:96390332-96434143

Previous symbols: [ "NEC1" ]

Links

ENSG00000175426 ∙ NCBI:5122 ∙ OMIM:162150 ∙ HGNC:8743 ∙ Uniprot:P29120 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• obesity due to prohormone convertase I deficiency (Supportive), mode of inheritance: AR
• obesity due to prohormone convertase I deficiency (Strong), mode of inheritance: AR
• obesity due to prohormone convertase I deficiency (Strong), mode of inheritance: AR
• obesity due to prohormone convertase I deficiency (Definitive), mode of inheritance: AR
• obesity due to prohormone convertase I deficiency (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Proprotein convertase 1/3 deficiency	AD	Endocrine; Gastrointestinal	Presentations may be diverse, and interventions such as early parenteral nutrition may be necessary; Endocrinologic interventions can allow induction of secondary sex characteristic and reproduction; Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial	Endocrine; Gastrointestinal	7477119; 9207799; 14617756; 17595246; 35528826
Endocrinologic interventions can allow induction of secondary sex characteristic and reproduction

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PCSK1 gene.

• not provided (119 variants)
• Obesity due to prohormone convertase I deficiency (96 variants)
• Monogenic Non-Syndromic Obesity (51 variants)
• PCSK1-related condition (22 variants)
• not specified (17 variants)
• Inborn genetic diseases (13 variants)
• Body mass index quantitative trait locus 12;Obesity due to prohormone convertase I deficiency (7 variants)
• Obesity due to prohormone convertase I deficiency;Body mass index quantitative trait locus 12 (1 variants)
• Body mass index quantitative trait locus 12 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PCSK1 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			9	18		27
missense		3	72	5	1	81
nonsense	1	3				4
start loss						0
frameshift	1	2				3
inframe indel						0
splice donor/acceptor (+/-2bp)		4				4
splice region			1	4		5
non coding			48	19	27	94
Total	2	12	129	42	28

Highest pathogenic variant AF is 0.0000197

Variants in PCSK1

This is a list of pathogenic ClinVar variants found in the PCSK1 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-96390365-G-A		Obesity due to prohormone convertase I deficiency	Uncertain significance (Jan 13, 2018)
5-96390367-C-T		Obesity due to prohormone convertase I deficiency	Uncertain significance (Jan 13, 2018)
5-96390390-T-C		Obesity due to prohormone convertase I deficiency	Uncertain significance (Jan 12, 2018)
5-96390419-T-C		Obesity due to prohormone convertase I deficiency	Uncertain significance (Jan 12, 2018)
5-96390713-T-C		Obesity due to prohormone convertase I deficiency • Monogenic Non-Syndromic Obesity	Uncertain significance (Jan 13, 2018)
5-96390814-C-T		Obesity due to prohormone convertase I deficiency	Uncertain significance (Jan 13, 2018)
5-96390835-G-A		Monogenic Non-Syndromic Obesity • Obesity due to prohormone convertase I deficiency	Uncertain significance (Jan 13, 2018)
5-96390886-C-T		Obesity due to prohormone convertase I deficiency	Uncertain significance (Jan 12, 2018)
5-96390982-T-C		Monogenic Non-Syndromic Obesity • Obesity due to prohormone convertase I deficiency	Uncertain significance (Jun 14, 2016)
5-96391034-G-A		Obesity due to prohormone convertase I deficiency	Uncertain significance (Jan 12, 2018)
5-96391089-C-T		Obesity due to prohormone convertase I deficiency • Monogenic Non-Syndromic Obesity	Uncertain significance (Jan 13, 2018)
5-96391147-A-T		Monogenic Non-Syndromic Obesity • Obesity due to prohormone convertase I deficiency	Uncertain significance (Jun 14, 2016)
5-96391159-C-T		Obesity due to prohormone convertase I deficiency • Monogenic Non-Syndromic Obesity	Uncertain significance (Jun 14, 2016)
5-96391268-C-T		Monogenic Non-Syndromic Obesity • Obesity due to prohormone convertase I deficiency	Uncertain significance (Jun 14, 2016)
5-96391430-T-C		Obesity due to prohormone convertase I deficiency • Monogenic Non-Syndromic Obesity	Uncertain significance (Jun 14, 2016)
5-96391471-A-G		Monogenic Non-Syndromic Obesity • Obesity due to prohormone convertase I deficiency	Likely benign (Jun 14, 2016)
5-96391558-G-A		Monogenic Non-Syndromic Obesity • Obesity due to prohormone convertase I deficiency	Uncertain significance (Jun 14, 2016)
5-96391587-T-G		Obesity due to prohormone convertase I deficiency • Monogenic Non-Syndromic Obesity	Uncertain significance (Jan 13, 2018)
5-96391600-G-A		Monogenic Non-Syndromic Obesity • Obesity due to prohormone convertase I deficiency	Uncertain significance (Jan 13, 2018)
5-96391629-G-C		Obesity due to prohormone convertase I deficiency	Uncertain significance (Jan 13, 2018)
5-96391668-T-A		Monogenic Non-Syndromic Obesity • Obesity due to prohormone convertase I deficiency	Uncertain significance (Jun 14, 2016)
5-96391694-T-C		Obesity due to prohormone convertase I deficiency	Uncertain significance (Jan 12, 2018)
5-96391769-C-T		Monogenic Non-Syndromic Obesity • Obesity due to prohormone convertase I deficiency	Uncertain significance (Jan 12, 2018)
5-96391770-G-A		Obesity due to prohormone convertase I deficiency • Monogenic Non-Syndromic Obesity	Uncertain significance (Jan 12, 2018)
5-96391837-A-G		Monogenic Non-Syndromic Obesity • Obesity due to prohormone convertase I deficiency	Uncertain significance (Jun 14, 2016)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PCSK1	protein_coding	protein_coding	ENST00000311106	14	43729

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.74e-9	0.999	125709	0	39	125748	0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.47	328	412	0.796	0.0000226	4964
Missense in Polyphen		111	185.64	0.59793		2160
Synonymous	-0.506	165	157	1.05	0.00000959	1432
Loss of Function	2.94	21	41.4	0.507	0.00000226	451

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000427	0.000427
Ashkenazi Jewish	0.0000995	0.0000992
East Asian	0.000218	0.000217
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000141	0.000141
Middle Eastern	0.000218	0.000217
South Asian	0.000229	0.000229
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues. Substrates include POMC, renin, enkephalin, dynorphin, somatostatin, insulin and AGRP. {ECO:0000250|UniProtKB:P63239}.
• Disease: DISEASE: Proprotein convertase 1 deficiency (PC1 deficiency) [MIM:600955]: Characterized by obesity, hypogonadism, hypoadrenalism, reactive hypoglycemia as well as marked small- intestinal absorptive dysfunction It is due to impaired processing of prohormones. {ECO:0000269|PubMed:14617756, ECO:0000269|PubMed:17595246, ECO:0000269|PubMed:9207799}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Prader-Willi and Angelman Syndrome;Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP);Incretin synthesis, secretion, and inactivation;Peptide hormone metabolism;Synthesis, secretion, and deacylation of Ghrelin;Metabolism of proteins;Insulin processing;Peptide hormone biosynthesis (Consensus)

Recessive Scores

• pRec: 0.340

Intolerance Scores

• loftool: 0.271
• rvis_EVS: -0.42
• rvis_percentile_EVS: 25.73

Haploinsufficiency Scores

• pHI: 0.351
• hipred: Y
• hipred_score: 0.663
• ghis: 0.438

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.808

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pcsk1
• 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); reproductive system 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); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; limbs/digits/tail phenotype; digestive/alimentary phenotype; muscle 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; growth/size/body region phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: proteolysis;cell-cell signaling;protein processing;peptide hormone processing;peptide biosynthetic process
• Cellular component: extracellular space;membrane;transport vesicle;secretory granule lumen;neuron projection
• Molecular function: serine-type endopeptidase activity;identical protein binding