11-279352-C-G

Variant names:

• chr11-279352-C-G
• rs1181620644
• NM_001276700.2:c.55C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001276700.2(NLRP6):​c.55C>G​(p.Arg19Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000175 in 1,142,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: NLRP6 NM_001276700.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.250
• Publications: 0 publications found

Genes affected

NLRP6 (HGNC:22944): (NLR family pyrin domain containing 6) 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]

ENSG00000293500 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31781662).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001276700.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP6	NM_001276700.2	MANE Select	c.55C>G	p.Arg19Gly	missense	Exon 2 of 8	NP_001263629.1	P59044-2
	NLRP6	NM_138329.2		c.55C>G	p.Arg19Gly	missense	Exon 2 of 8	NP_612202.2	P59044-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP6	ENST00000534750.6	TSL:2 MANE Select	c.55C>G	p.Arg19Gly	missense	Exon 2 of 8	ENSP00000433617.1	P59044-2
	NLRP6	ENST00000312165.5	TSL:1	c.55C>G	p.Arg19Gly	missense	Exon 2 of 8	ENSP00000309767.4	P59044-1
	NLRP6	ENST00000527946.1	TSL:4	n.294C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000175 AC: 2 AN: 1142508 Hom.: 0 Cov.: 35 AF XY: 0.00000183 AC XY: 1 AN XY: 547628

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23176

American (AMR) AF: 0.00 AC: 0 AN: 8538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15548

East Asian (EAS) AF: 0.00 AC: 0 AN: 26628

South Asian (SAS) AF: 0.00 AC: 0 AN: 39542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3064

European-Non Finnish (NFE) AF: 0.00000210 AC: 2 AN: 952970

Other (OTH) AF: 0.00 AC: 0 AN: 46240

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T
Eigen	Benign	0.063
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.85	T
PhyloP100		-0.25
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.29
MutPred		0.70		Loss of stability (P = 0.083)
MVP		0.37
ClinPred		0.82	D
GERP RS		2.7
Varity_R		0.53
gMVP		0.55
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1181620644; hg19: chr11-279352;