NLRP6

protein-coding

NLR family pyrin domain containing 6, the group of Pyrin domain containing|NLR family

Gene summary

The protein encoded by this gene binds arginine-vasopressin and may be involved in the arginine-vasopressin-mediated regulation of renal salt-water balance. The encoded protein also mediates inflammatory responses in the colon to allow recovery from intestinal epithelial damage and protects against tumorigenesis and the development of colitis. Finally, this protein can increase activation of NF-kappa-B, activation of CASP1 through interaction with ASC, and cAMP accumulation. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2013]

Previous symbols:

NALP6

MANE transcript

NM_001276700.2

Inheritance

—

ClinVar variants

U:153B:17

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr11:278,407-285,388

External References & Databases

Ensembl (ENSG00000174885)

Transcript & Mutation Effects

hg38 • Region Span ~7.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NLRP6 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 147

not providedTotal: 39

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001276700.2. 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			7 clinvar	1 clinvar	1 clinvar	9
missense			144 clinvar	14 clinvar	1 clinvar	159
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	153	15	2	170

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001276700.2	RefSeq	NP_001263629.1	8	MANE Select
ENST00000534750.6	Ensembl	ENSP00000433617.1	8	MANE Select
NM_138329.2	RefSeq	NP_612202.2	8	Standard
ENST00000312165.5	Ensembl	ENSP00000309767.4	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

NOD-like receptor signaling pathway - Homo sapiens (human)

Biological Process

negative regulation of inflammatory response to antigenic stimulus
inflammatory response
G protein-coupled receptor signaling pathway
response to bacterium
regulation of autophagy

Molecular Function

vasopressin receptor activity
ATP binding

Cellular Component

plasma membrane
nuclear membrane
inflammasome complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000312165
Coding exons: 8
Length: 6995
Individuals with no LoFs: 125667
Homozygous LoFs: 0
Heterozygous LoFs: 79
Defined: 125746
p: 0.000314

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.76	393	504	0.779	0.0000328	5566
Missense (PolyPhen)		88	134.52	0.65417		1815
Synonymous	1.24	218	243	0.899	0.0000168	1938
Loss of Function	2.99	11	28.1	0.391	0.00000153	314

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00050	0.00049	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000055	0.000054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00048	0.00047	rare
South Asian	0.00017	0.00016	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: As the sensor component of the NLRP6 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens and other damage-associated signals, initiates the formation of the inflammasome polymeric complex, made of NLRP6, PYCARD and CASP1 (and possibly CASP4 and CASP5). Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1- catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu. The precise NLRP6 activation stimulus has not been identified yet (By similarity) (PubMed:12387869). Essential for gut mucosal self-renewal and proliferation. Maintains intestinal homeostasis and a healthy intestinal microbiota. This function is, at least partially, mediated by IL18, and not IL1B, produced by nonhematopoietic cells. Influences intestinal barrier function and microbial homeostasis through the regulation of goblet cell mucus secretion. Acts by promoting autophagy in goblet cells, an essential step for mucus granule exocytosis. Its role in goblet cell physiology is inflammasome- dependent, but IL1B- and IL18-independent. During systemic bacterial infections, may negatively regulate inflammatory signaling and inhibit the influx of monocytes and neutrophils to the circulation and to the peritoneum. May promote peripheral nerve recovery following injury via an inflammasome-independent mechanism (By similarity). {ECO:0000250|UniProtKB:Q91WS2, ECO:0000250|UniProtKB:Q96P20, ECO:0000269|PubMed:12387869}.;

Recessive Scores

pRec: 0.110

Intolerance Scores

LoFtool: 0.530
RVIS EVS: 1.27
RVIS percentile EVS: 93.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.377

Gene Damage Prediction

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