CARD14

protein-coding

caspase recruitment domain family member 14, the group of PDZ domain containing|Membrane associated guanylate kinases|Caspase recruitment domain containing

Gene summary

This gene encodes a caspase recruitment domain-containing protein that is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. Members of this protein family are scaffold proteins that are involved in a diverse array of cellular processes including cellular adhesion, signal transduction and cell polarity control. This protein has been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

Previous symbols:

PSORS2

MANE transcript

NM_001366385.1

Inheritance

ClinVar variants

P:14U:693B:396

Top phenotype

Pityriasis rubra pilaris; Psoriasis 2

gnomAD constraint

pLI —, LoF o/e 0.75

Max pathogenic AF

—

Genomic locus

chr17:80,169,992-80,216,073

External References & Databases

Ensembl (ENSG00000141527)

Transcript & Mutation Effects

hg38 • Region Span ~46.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

psoriasis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011269

Submitter: Genomics England PanelApp

familial pityriasis rubra pilarisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008251

Submitter: Genomics England PanelApp

familial pityriasis rubra pilarisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008251

Submitter: Orphanet

familial pityriasis rubra pilarisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008251

Submitter: G2P

psoriasis 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011269

Submitter: G2P

familial pityriasis rubra pilarisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008251

Submitter: Labcorp Genetics (formerly Invitae)

psoriasis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011269

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Pityriasis rubra pilaris; Psoriasis 2AD

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: 8178173; 15689454; 22521418

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CARD14 variants in ClinVar

10 Conditions Cataloged

Psoriasis 2Total: 1207

Pityriasis rubra pilarisTotal: 1205

not providedTotal: 210

Inborn genetic diseasesTotal: 187

not specifiedTotal: 185

Autoinflammatory syndromeTotal: 132

CARD14-related disorderTotal: 67

Papulosquamous eruptionsTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001366385.1. 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			19 clinvar	297 clinvar	9 clinvar	325
missense	9 clinvar	2 clinvar	593 clinvar	87 clinvar	2 clinvar	693
nonsense			26 clinvar	1 clinvar		27
start loss						0
frameshift		1 clinvar	32 clinvar			33
splice donor/acceptor (+/-2bp)	2 clinvar		23 clinvar			25
Total	11	3	693	385	11	1103

Highest pathogenic variant AF is 0.000006840647

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001366385.1	RefSeq	NP_001353314.1	20	MANE Select
ENST00000648509.2	Ensembl	ENSP00000498071.1	20	MANE Select
NM_001257970.1	RefSeq	NP_001244899.1	14	Standard
NM_024110.4	RefSeq	NP_077015.2	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

NF-kappa B signaling pathway - Homo sapiens (human)
Apoptosis-related network due to altered Notch3 in ovarian cancer

Biological Process

positive regulation of protein phosphorylation
apoptotic process
activation of NF-kappaB-inducing kinase activity
tumor necrosis factor-mediated signaling pathway
negative regulation of apoptotic process

Molecular Function

CARD domain binding

Cellular Component

cytoplasm
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000573882
Coding exons: 20
Length: 39340
Individuals with no LoFs: 125589
Homozygous LoFs: 0
Heterozygous LoFs: 159
Defined: 125748
p: 0.000632

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.608	576	619	0.931	0.0000416	6456
Missense (PolyPhen)		164	175.01	0.93708		1900
Synonymous	-1.39	298	269	1.11	0.0000188	1960
Loss of Function	1.58	36	47.8	0.753	0.00000242	535

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00094	0.00092	rare
Latino/Admixed American	0.00079	0.00075	rare
Ashkenazi Jewish	0.00090	0.00089	rare
East Asian	0.0019	0.0019	notable
Finnish	0.000054	0.000046	rare
European (Non-Finnish)	0.00041	0.00040	rare
South Asian	0.00088	0.00088	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a scaffolding protein that can activate the inflammatory transcription factor NF-kappa-B and p38/JNK MAP kinase signaling pathways. Forms a signaling complex with BCL10 and MALT1, and activates MALT1 proteolytic activity and inflammatory gene expression. MALT1 is indispensable for CARD14- induced activation of NF-kappa-B and p38/JNK MAP kinases (PubMed:11278692, PubMed:21302310, PubMed:27113748, PubMed:27071417). May play a role in signaling mediated by TRAF2, TRAF3 and TRAF6 and protects cells against apoptosis. {ECO:0000269|PubMed:11278692, ECO:0000269|PubMed:21302310, ECO:0000269|PubMed:27071417, ECO:0000269|PubMed:27113748}.;
Disease: DISEASE: Psoriasis 2 (PSORS2) [MIM:602723]: A common, chronic inflammatory disease of the skin with multifactorial etiology. It is characterized by red, scaly plaques usually found on the scalp, elbows and knees. These lesions are caused by abnormal keratinocyte proliferation and infiltration of inflammatory cells into the dermis and epidermis. {ECO:0000269|PubMed:22521418, ECO:0000269|PubMed:22521419, ECO:0000269|PubMed:26358359, ECO:0000269|PubMed:27071417, ECO:0000269|PubMed:27113748}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Pityriasis rubra pilaris (PRP) [MIM:173200]: A rare, papulosquamous skin disease characterized by the appearance of keratotic follicular papules, well-demarcated salmon-colored erythematous plaques covered with fine powdery scales interspersed with distinct islands of uninvolved skin, and palmoplantar keratoderma. Most cases are sporadic. The rare familial cases show autosomal dominant inheritance with incomplete penetrance and variable expression. Familial PRP usually presents at birth or appears during the first years of life and runs a chronic course. It is characterized by prominent follicular hyperkeratosis, diffuse palmoplantar keratoderma, and erythema. {ECO:0000269|PubMed:22703878, ECO:0000269|PubMed:27760266}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.128

Intolerance Scores

LoFtool: 0.832
RVIS EVS: 0.89
RVIS percentile EVS: 89.08

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.705

Gene Damage Prediction

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