PREPL

prolyl endopeptidase like

Basic information

Region (hg38): 2:44316281-44361862

Links

ENSG00000138078 ∙ NCBI:9581 ∙ OMIM:609557 ∙ HGNC:30228 ∙ Uniprot:Q4J6C6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypotonia-cystinuria syndrome (Strong), mode of inheritance: AR
• myasthenic syndrome, congenital, 22 (Moderate), mode of inheritance: AR
• myasthenic syndrome, congenital, 22 (Moderate), mode of inheritance: AR
• myasthenic syndrome, congenital, 22 (Moderate), mode of inheritance: AR
• myasthenic syndrome, congenital, 22 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Myasthenic syndrome, congenital 22	AR	Neurologic	Medical treatment with acetylcholine esterase inhibitors has been described as beneficial in one individual; In infancy, the use of apnea monitors may be indicated; Agents that affect neuromuscular transmission and exacerbate myasthenic manifestations should be avoided	Neurologic	24610330

ClinVar

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

• Myasthenic syndrome, congenital, 22 (16 variants)
• Cystinuria (6 variants)
• Cystine urolithiasis (1 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PREPL 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			3	140	3	146
missense		1	283	10	6	300
nonsense	6	5	1			12
start loss			3			3
frameshift	11	4				15
inframe indel			2			2
splice donor/acceptor (+/-2bp)		11				11
splice region			16	30	2	48
non coding	6	5	30	81	43	165
Total	23	26	322	231	52

Highest pathogenic variant AF is 0.0000132

Variants in PREPL

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

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

Position	Type	Phenotype	Significance	ClinVar
2-44319992-A-G			Benign (Aug 20, 2019)
2-44320003-A-G			Benign (Aug 20, 2019)
2-44320097-G-C			Benign (Dec 01, 2020)
2-44320183-T-C		Cystinuria	Likely benign (Dec 13, 2021)
2-44320188-T-A		Cystinuria	Benign (Apr 20, 2023)
2-44320194-A-T		Cystinuria	Likely benign (Oct 15, 2023)
2-44320207-G-T		Cystinuria	Uncertain significance (Jan 12, 2018)
2-44320221-C-A		Cystinuria	Pathogenic (Jul 28, 2023)
2-44320221-C-T		Cystine urolithiasis • Cystinuria • SLC3A1-related disorder	Conflicting classifications of pathogenicity (Dec 04, 2023)
2-44320222-G-T		Cystinuria	Conflicting classifications of pathogenicity (Apr 03, 2018)
2-44320234-A-G		Cystinuria	Likely benign (Mar 12, 2023)
2-44320238-C-G		Cystinuria	Uncertain significance (May 22, 2022)
2-44320265-G-C		Cystinuria	Uncertain significance (Aug 16, 2023)
2-44320279-CAG-C		Cystinuria	Pathogenic (May 17, 2022)
2-44320282-G-A			Likely benign (Sep 22, 2017)
2-44320282-G-T		Cystinuria	Uncertain significance (Aug 16, 2023)
2-44320283-G-A		Cystinuria	Uncertain significance (Dec 19, 2023)
2-44320298-T-C		Cystinuria	Conflicting classifications of pathogenicity (Jun 06, 2023)
2-44320323-T-G		Cystinuria	Uncertain significance (Jan 13, 2018)
2-44320325-T-C		Cystinuria	Likely pathogenic (Dec 31, 2018)
2-44320329-CA-C		Cystinuria • SLC3A1-related disorder	Pathogenic/Likely pathogenic (Jul 12, 2023)
2-44320329-CAA-C		Cystinuria	Pathogenic (Aug 09, 2019)
2-44320337-C-T		Cystinuria • SLC3A1-related disorder	Likely benign (Mar 26, 2023)
2-44320348-C-T		Cystinuria	Conflicting classifications of pathogenicity (Apr 02, 2023)
2-44320349-G-A		Cystinuria	Uncertain significance (Aug 30, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PREPL	protein_coding	protein_coding	ENST00000409936	14	45582

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.16e-13	0.608	125620	0	128	125748	0.000509

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-2.50	539	399	1.35	0.0000211	4833
Missense in Polyphen		143	112.27	1.2738		1333
Synonymous	-2.23	174	140	1.24	0.00000766	1308
Loss of Function	1.58	25	35.1	0.712	0.00000170	467

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00168	0.00168
Ashkenazi Jewish	0.00130	0.00129
East Asian	0.000818	0.000761
Finnish	0.0000925	0.0000924
European (Non-Finnish)	0.000248	0.000246
Middle Eastern	0.000818	0.000761
South Asian	0.000655	0.000653
Other	0.00115	0.00114

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Probable serine peptidase whose precise substrate specificity remains unclear. Does not cleave peptides after a arginine or lysine residue. May play a role in the regulation of synaptic vesiscle exocytosis (PubMed:24610330). {ECO:0000269|PubMed:16143824, ECO:0000269|PubMed:16385448, ECO:0000269|PubMed:24610330}.
• Disease: DISEASE: Myasthenic syndrome, congenital, 22 (CMS22) [MIM:616224]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features include easy fatigability and muscle weakness. CMS22 is an autosomal recessive form characterized by neonatal hypotonia. {ECO:0000269|PubMed:24610330}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Recessive Scores

• pRec: 0.109

Intolerance Scores

• loftool: 0.0602
• rvis_EVS: -0.84
• rvis_percentile_EVS: 11.48

Haploinsufficiency Scores

• pHI: 0.374
• hipred: N
• hipred_score: 0.339
• ghis: 0.646

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.944

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Prepl
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); muscle phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: proteolysis;regulation of synaptic vesicle exocytosis
• Cellular component: Golgi apparatus;cytosol;cytoskeleton
• Molecular function: serine-type endopeptidase activity;protein binding;serine-type exopeptidase activity