CARD8

protein-coding

caspase recruitment domain family member 8, the group of Caspase recruitment domain containing

Gene summary

The protein encoded by this gene belongs to the caspase recruitment domain (CARD)-containing family of proteins, which are involved in pathways leading to activation of caspases or nuclear factor kappa-B (NFKB). This protein may be a component of the inflammasome, a protein complex that plays a role in the activation of proinflammatory caspases. It is thought that this protein acts as an adaptor molecule that negatively regulates NFKB activation, CASP1-dependent IL1B secretion, and apoptosis. Polymorphisms in this gene may be associated with a susceptibility to rheumatoid arthritis. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, May 2010]

MANE transcript

NM_001184900.3

Inheritance

ClinVar variants

P:1U:277B:117

Top phenotype

Inflammatory bowel disease 30

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr19:48,180,770-48,255,946

External References & Databases

Ensembl (ENSG00000105483)

Transcript & Mutation Effects

hg38 • Region Span ~75.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

inflammatory bowel disease 30LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0033643

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Inflammatory bowel disease 30AD

Manifestation: Allergy/Immunology/Infectious; Gastrointestinal

Intervention: Allergy/Immunology/Infectious; Gastrointestinal

Rationale: The condition can involve sequelae of inflammatory bowel disease, and medical management (eg, with steroids, anti-IL1B monoclonal antibodies) have been described as beneficial

Refs: 29408806

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CARD8 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 441

not specifiedTotal: 73

CARD8-related disorderTotal: 14

Inflammatory bowel disease 30Total: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001184900.3. 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			4 clinvar	91 clinvar	7 clinvar	102
missense			234 clinvar	12 clinvar	6 clinvar	252
nonsense			7 clinvar			7
start loss			2 clinvar			2
frameshift		1 clinvar	21 clinvar			22
splice donor/acceptor (+/-2bp)			9 clinvar	1 clinvar		10
Total	0	1	277	104	13	395

Highest pathogenic variant AF is 0.000027348522

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 119 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001184900.3	RefSeq	NP_001171829.1	11	MANE Select
ENST00000651546.1	Ensembl	ENSP00000499211.1	11	MANE Select
NM_001184901.1	RefSeq	NP_001171830.1	10	Standard
NM_001184902.2	RefSeq	NP_001171831.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

NOD-like receptor signaling pathway - Homo sapiens (human)
Nucleotide-binding Oligomerization Domain (NOD) pathway

Biological Process

apoptotic process
activation of cysteine-type endopeptidase activity involved in apoptotic process
negative regulation of tumor necrosis factor-mediated signaling pathway
negative regulation of lipopolysaccharide-mediated signaling pathway
negative regulation of NF-kappaB transcription factor activity

Molecular Function

protein binding
cysteine-type endopeptidase activator activity involved in apoptotic process
NACHT domain binding
protein homodimerization activity
CARD domain binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000391898
Coding exons: 11
Length: 75177
Individuals with no LoFs: 125632
Homozygous LoFs: 2
Heterozygous LoFs: 112
Defined: 125746
p: 0.000453

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.923	251	296	0.849	0.0000162	3520
Missense (PolyPhen)		84	96.456	0.87087		1225
Synonymous	0.178	112	114	0.979	0.00000617	1019
Loss of Function	2.01	13	23.5	0.552	0.00000109	287

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00065	0.00065	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00011	0.000097	rare
South Asian	0.0030	0.0029	notable
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Inhibits NF-kappa-B activation. May participate in a regulatory mechanism that coordinates cellular responses controlled by NF-kappa-B transcription factor. May be a component of the inflammasome, a protein complex which also includes PYCARD, NALP2 and CASP1 and whose function would be the activation of proinflammatory caspases.;

Recessive Scores

pRec: 0.0634

Intolerance Scores

LoFtool: 0.983
RVIS EVS: 1.18
RVIS percentile EVS: 92.79

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.783

Gene Damage Prediction

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