CAST

calpastatin

Basic information

Region (hg38): 5:96247756-96779595

Links

ENSG00000310517 ∙ NCBI:831 ∙ OMIM:114090 ∙ HGNC:1515 ∙ Uniprot:P20810 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome (Strong), mode of inheritance: AR
• peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome (Moderate), mode of inheritance: AR
• peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome (Strong), mode of inheritance: AR
• peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome (Supportive), mode of inheritance: AR
• peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome (Strong), mode of inheritance: AR
• peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Peeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads (PLACK)	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Dermatologic	25683118

ClinVar

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

• not_provided (91 variants)
• Inborn_genetic_diseases (77 variants)
• CAST-related_disorder (18 variants)
• Peeling_skin-leukonuchia-acral_punctate_keratoses-cheilitis-knuckle_pads_syndrome (13 variants)
• not_specified (2 variants)
• ERAP1-related_disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CAST gene is commonly pathogenic or not. These statistics are base on transcript: NM_000001750.7. 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			2	21	5	28
missense			79	11	8	98
nonsense	3	4				7
start loss						0
frameshift	3	1				4
splice donor/acceptor (+/-2bp)		1				1
Total	6	6	81	32	13

Highest pathogenic variant AF is 0.00000703848

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CAST	protein_coding	protein_coding	ENST00000395812	29	254329

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.12e-12	0.996	125691	0	57	125748	0.000227

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.384	402	381	1.06	0.0000192	4827
Missense in Polyphen		141	140.13	1.0062		1991
Synonymous	0.515	130	138	0.944	0.00000752	1434
Loss of Function	2.74	26	46.1	0.564	0.00000195	665

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000315	0.000308
Ashkenazi Jewish	0.000200	0.000198
East Asian	0.0000547	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.000268	0.000264
Middle Eastern	0.0000547	0.0000544
South Asian	0.000640	0.000588
Other	0.000165	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Specific inhibition of calpain (calcium-dependent cysteine protease). Plays a key role in postmortem tenderization of meat and have been proposed to be involved in muscle protein degradation in living tissue.
• Disease: DISEASE: Peeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads (PLACK) [MIM:616295]: An autosomal recessive disease characterized by generalized, continuous shedding of the outer layers of the epidermis, leukonychia, acral punctate keratosis, cheilitis, knuckle pads with multiple hyperkeratotic micropapules involving the interphalangeal joints, and palmoplantar keratoderma. {ECO:0000269|PubMed:25683118}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer,s disease models;Neurodegenerative Diseases;Disease;mcalpain and friends in cell motility;Extracellular matrix organization;Degradation of the extracellular matrix (Consensus)

Recessive Scores

• pRec: 0.338

Intolerance Scores

• loftool: 0.963
• rvis_EVS: 0.71
• rvis_percentile_EVS: 85.82

Haploinsufficiency Scores

• pHI: 0.280
• hipred: N
• hipred_score: 0.429
• ghis: 0.387

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.354

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cast
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); skeleton phenotype; immune system phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs 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); hematopoietic 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: inhibition of cysteine-type endopeptidase activity;presynaptic active zone organization;negative regulation of type B pancreatic cell apoptotic process
• Cellular component: endoplasmic reticulum;cytosol;membrane
• Molecular function: protease binding;RNA binding;endopeptidase inhibitor activity;protein binding;calcium-dependent cysteine-type endopeptidase inhibitor activity;cadherin binding