11-280126-C-T

Variant names:

• chr11-280126-C-T
• rs772101945
• NM_001276700.2:c.392C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001276700.2(NLRP6):​c.392C>T​(p.Ala131Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000202 in 1,535,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: NLRP6 NM_001276700.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0490

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19009846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP6	NM_001276700.2	c.392C>T	p.Ala131Val	missense_variant	Exon 4 of 8	ENST00000534750.6	NP_001263629.1
NLRP6	NM_138329.2	c.392C>T	p.Ala131Val	missense_variant	Exon 4 of 8		NP_612202.2
NLRP6	XR_930848.2	n.555C>T		non_coding_transcript_exon_variant	Exon 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP6	ENST00000534750.6	c.392C>T	p.Ala131Val	missense_variant	Exon 4 of 8	2	NM_001276700.2	ENSP00000433617.1
NLRP6	ENST00000312165.5	c.392C>T	p.Ala131Val	missense_variant	Exon 4 of 8	1		ENSP00000309767.4

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000437 AC: 6 AN: 137336 Hom.: 0 AF XY: 0.0000263 AC XY: 2 AN XY: 76018

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.0000497

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000576

Gnomad OTH exome AF: 0.000265

GnomAD4 exome AF: 0.0000152 AC: 21 AN: 1383424 Hom.: 0 Cov.: 32 AF XY: 0.0000117 AC XY: 8 AN XY: 683848

Gnomad4 AFR exome AF: 0.0000337

Gnomad4 AMR exome AF: 0.0000976

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000130

Gnomad4 OTH exome AF: 0.0000351

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74364

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.0000349 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.392C>T (p.A131V) alteration is located in exon 4 (coding exon 4) of the NLRP6 gene. This alteration results from a C to T substitution at nucleotide position 392, causing the alanine (A) at amino acid position 131 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.055	.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.61	T
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.24
Sift	Benign	0.046	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.99	.;D
Vest4		0.31
MutPred		0.29		Loss of disorder (P = 0.0912);Loss of disorder (P = 0.0912);
MVP		0.15
ClinPred		0.24	T
GERP RS		2.6
Varity_R		0.089
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs772101945; hg19: chr11-280126;