CAST

protein-coding

calpastatin

Gene summary

The protein encoded by this gene is an endogenous calpain (calcium-dependent cysteine protease) inhibitor. It consists of an N-terminal domain L and four repetitive calpain-inhibition domains (domains 1-4), and it is involved in the proteolysis of amyloid precursor protein. The calpain/calpastatin system is involved in numerous membrane fusion events, such as neural vesicle exocytosis and platelet and red-cell aggregation. The encoded protein is also thought to affect the expression levels of genes encoding structural or regulatory proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]

MANE transcript

NM_001750.7

Inheritance

ClinVar variants

P:14U:121B:49

Top phenotype

Peeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads (PLACK)

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr5:96,247,756-96,779,595

External References & Databases

Ensembl (ENSG00000310517)

Transcript & Mutation Effects

hg38 • Region Span ~531.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014574

Submitter: Orphanet

peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014574

Submitter: Ambry Genetics

peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014574

Submitter: Labcorp Genetics (formerly Invitae)

peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014574

Submitter: Genomics England PanelApp

peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014574

Submitter: G2P

Clinical Genomic Database (CGD)

Peeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads (PLACK)AR

Manifestation: Dermatologic

Intervention: General

Rationale: 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

Refs: 25683118

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CAST variants in ClinVar

6 Conditions Cataloged

not providedTotal: 108

Inborn genetic diseasesTotal: 90

CAST-related disorderTotal: 21

Peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndromeTotal: 14

not specifiedTotal: 8

ERAP1-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001750.7. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	26 clinvar	4 clinvar	35
missense			101 clinvar	11 clinvar	8 clinvar	120
nonsense	3 clinvar	4 clinvar	1 clinvar			8
start loss						0
frameshift	3 clinvar	1 clinvar				4
splice donor/acceptor (+/-2bp)		3 clinvar	14 clinvar			17
Total	6	8	121	37	12	184

Highest pathogenic variant AF is 0.0000070384776

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001750.7	RefSeq	NP_001741.4	31	MANE Select
NM_001042440.5	RefSeq	NP_001035905.1	29	Standard
NM_001042441.3	RefSeq	NP_001035906.1	30	Standard
NM_001042442.3	RefSeq	NP_001035907.1	30	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer,s disease models
Neurodegenerative Diseases
Disease
mcalpain and friends in cell motility
Extracellular matrix organization

Biological Process

inhibition of cysteine-type endopeptidase activity
presynaptic active zone organization
negative regulation of type B pancreatic cell apoptotic process

Molecular Function

protease binding
RNA binding
endopeptidase inhibitor activity
protein binding
calcium-dependent cysteine-type endopeptidase inhibitor activity

Cellular Component

endoplasmic reticulum
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000395812
Coding exons: 29
Length: 254329
Individuals with no LoFs: 125691
Homozygous LoFs: 0
Heterozygous LoFs: 57
Defined: 125748
p: 0.000227

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.384	402	381	1.06	0.0000192	4827
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00032	0.00031	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00027	0.00026	rare
South Asian	0.00064	0.00059	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.338

Intolerance Scores

LoFtool: 0.963
RVIS EVS: 0.71
RVIS percentile EVS: 85.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.354

Gene Damage Prediction

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