CASP14

protein-coding

caspase 14, the group of Caspases

Gene summary

This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This caspase has been shown to be processed and activated by caspase 8 and caspase 10 in vitro, and by anti-Fas agonist antibody or TNF-related apoptosis inducing ligand in vivo. The expression and processing of this caspase may be involved in keratinocyte terminal differentiation, which is important for the formation of the skin barrier. [provided by RefSeq, Jul 2008]

MANE transcript

NM_012114.3

Inheritance

ClinVar variants

U:61B:13

Top phenotype

Ichthyosis, congenital, autosomal recessive 12

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr19:15,049,480-15,058,293

External References & Databases

Ensembl (ENSG00000105141)

Transcript & Mutation Effects

hg38 • Region Span ~8.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

Clinical Genomic Database (CGD)

Ichthyosis, congenital, autosomal recessive 12AR

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: 27494380

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CASP14 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 64

not providedTotal: 9

CASP14-related disorderTotal: 5

Ichthyosis, congenital, autosomal recessive 12Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012114.3. 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	3 clinvar	8
missense			58 clinvar	2 clinvar	2 clinvar	62
nonsense			3 clinvar			3
start loss						0
frameshift				1 clinvar		1
splice donor/acceptor (+/-2bp)						0
Total	0	0	61	8	5	74

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012114.3	RefSeq	NP_036246.1	6	MANE Select
ENST00000427043.4	Ensembl	ENSP00000393417.2	6	MANE Select
XM_011527861.2	RefSeq	XP_011526163.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vitamin D Receptor Pathway
Keratinization
Developmental Biology
DroToll-like
Formation of the cornified envelope

Biological Process

proteolysis
apoptotic process
epidermis development
intrinsic apoptotic signaling pathway in response to DNA damage
keratinization

Molecular Function

endopeptidase activity
cysteine-type endopeptidase activity
protein binding
cysteine-type endopeptidase activity involved in apoptotic process

Cellular Component

nucleus
cytoplasm
mitochondrion
cytosol
keratin filament

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000427043
Coding exons: 6
Length: 8910
Individuals with no LoFs: 125562
Homozygous LoFs: 0
Heterozygous LoFs: 183
Defined: 125745
p: 0.000728

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.175	156	150	1.04	0.00000925	1575
Missense (PolyPhen)		60	64.067	0.93653		683
Synonymous	-0.369	62	58.4	1.06	0.00000356	470
Loss of Function	0.804	10	13.1	0.761	7.92e-7	140

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.0027	0.0028	notable
Ashkenazi Jewish	0.0015	0.0015	notable
East Asian	0.0010	0.0010	notable
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00034	0.00034	rare
South Asian	0.000065	0.000065	rare
Other	0.0015	0.0015	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Non-apoptotic caspase involved in epidermal differentiation. Is the predominant caspase in epidermal stratum corneum (PubMed:15556625). Seems to play a role in keratinocyte differentiation and is required for cornification. Regulates maturation of the epidermis by proteolytically processing filaggrin (By similarity). In vitro has a preference for the substrate [WY]-X-X-D motif and is active on the synthetic caspase substrate WEHD-ACF (PubMed:16854378, PubMed:19960512). Involved in processing of prosaposin in the epidermis (By similarity). May be involved in retinal pigment epithelium cell barrier function (PubMed:25121097). Involved in DNA degradation in differentiated keratinocytes probably by cleaving DFFA/ICAD leading to liberation of DFFB/CAD (PubMed:24743736). {ECO:0000250|UniProtKB:O89094, ECO:0000269|PubMed:15301553, ECO:0000269|PubMed:15556625, ECO:0000269|PubMed:16854378, ECO:0000269|PubMed:19960512, ECO:0000269|PubMed:22825846, ECO:0000269|PubMed:24743736, ECO:0000305|PubMed:25121097}.;
Disease: DISEASE: Ichthyosis, congenital, autosomal recessive 12 (ARCI12) [MIM:617320]: A form of autosomal recessive congenital ichthyosis, a disorder of keratinization with abnormal differentiation and desquamation of the epidermis, resulting in abnormal skin scaling over the whole body. The main skin phenotypes are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur. Lamellar ichthyosis is a condition often associated with an embedment in a collodion-like membrane at birth; skin scales later develop, covering the entire body surface. Non-bullous congenital ichthyosiform erythroderma characterized by fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. {ECO:0000269|PubMed:27494380}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0980

Intolerance Scores

LoFtool: 0.825
RVIS EVS: -0.2
RVIS percentile EVS: 38.98

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.346

Gene Damage Prediction

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