NLRP12

protein-coding

NLR family pyrin domain containing 12, the group of Pyrin domain containing|NLR family

Gene summary

This gene encodes a member of the CATERPILLER family of cytoplasmic proteins. The encoded protein, which contains an N-terminal pyrin domain, a NACHT domain, a NACHT-associated domain, and a C-terminus leucine-rich repeat region, functions as an attenuating factor of inflammation by suppressing inflammatory responses in activated monocytes. Mutations in this gene cause familial cold autoinflammatory syndrome type 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

Previous symbols:

NALP12

MANE transcript

NM_144687.4

Inheritance

ClinVar variants

P:25U:860B:390

Top phenotype

Familial cold autoinflammatory syndrome 2

gnomAD constraint

pLI —, LoF o/e 1.04

Max pathogenic AF

—

Genomic locus

chr19:53,792,139-53,824,403

External References & Databases

Ensembl (ENSG00000142405)

Transcript & Mutation Effects

hg38 • Region Span ~32.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial cold autoinflammatory syndrome 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012724

Submitter: Orphanet

familial cold autoinflammatory syndrome 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012724

Submitter: Ambry Genetics

familial cold autoinflammatory syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012724

Submitter: Labcorp Genetics (formerly Invitae)

familial cold autoinflammatory syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012724

Submitter: PanelApp Australia

familial cold autoinflammatory syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012724

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Familial cold autoinflammatory syndrome 2AD

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Medical treatment (eg, with prednisone or colchicine) has been reported as effective in reducing fever

Refs: 18230725; 22753383; 27314497; 27633793

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NLRP12 variants in ClinVar

12 Conditions Cataloged

Familial cold autoinflammatory syndrome 2Total: 1227

not providedTotal: 284

Inborn genetic diseasesTotal: 176

not specifiedTotal: 152

Autoinflammatory syndromeTotal: 134

NLRP12-related disorderTotal: 69

Multisystem inflammatory syndrome in childrenTotal: 2

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_144687.4. 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			9 clinvar	301 clinvar	5 clinvar	315
missense		1 clinvar	753 clinvar	79 clinvar	2 clinvar	835
nonsense	1 clinvar	6 clinvar	35 clinvar	1 clinvar		43
start loss			3 clinvar			3
frameshift		14 clinvar	52 clinvar	2 clinvar		68
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	8 clinvar			11
Total	2	23	860	383	7	1275

Highest pathogenic variant AF is 0.0000427628

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_144687.4	RefSeq	NP_653288.1	10	MANE Select
ENST00000324134.11	Ensembl	ENSP00000319377.6	10	MANE Select
NM_001277126.2	RefSeq	NP_001264055.1	10	Standard
NM_001277129.1	RefSeq	NP_001264058.1	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

activation of cysteine-type endopeptidase activity involved in apoptotic process
signal transduction
negative regulation of signal transduction
negative regulation of protein autophosphorylation
negative regulation of NF-kappaB transcription factor activity

Molecular Function

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

Cellular Component

nucleus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000324134
Coding exons: 10
Length: 30792
Individuals with no LoFs: 125009
Homozygous LoFs: 3
Heterozygous LoFs: 736
Defined: 125748
p: 0.00294

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.71	729	610	1.20	0.0000402	6910
Missense (PolyPhen)		250	202.5	1.2345		2518
Synonymous	-2.50	326	273	1.19	0.0000195	2164
Loss of Function	-0.258	41	39.3	1.04	0.00000201	461

Population LoF Frequency

Population	CAF	p-value	Status
African	0.024	0.024	notable
Latino/Admixed American	0.0016	0.0016	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0017	0.0017	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.0015	0.0014	notable
South Asian	0.0029	0.0029	notable
Other	0.0024	0.0024	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May mediate activation of CASP1 via ASC and promote activation of NF-kappa-B via IKK.;
Disease: DISEASE: Familial cold autoinflammatory syndrome 2 (FCAS2) [MIM:611762]: A rare autosomal dominant systemic inflammatory disease characterized by recurrent episodes of maculopapular rash associated with arthralgias, myalgias, fever and chills, swelling of the extremities, and conjunctivitis after generalized exposure to cold. {ECO:0000269|PubMed:18230725}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.275
RVIS EVS: -0.45
RVIS percentile EVS: 24.22

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.230

Gene Damage Prediction

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