Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001277126.2(NLRP12):c.193G>C(p.Gly65Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G65A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Consequence

NLRP12
NM_001277126.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.90

Publications

0 publications found

Variant links:

Genes affected

NLRP12 (HGNC:22938): (NLR family pyrin domain containing 12) 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]

NLRP12 Gene-Disease associations (from GenCC):

familial cold autoinflammatory syndrome 2
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Laboratory for Molecular Medicine

NLRP12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277126.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NLRP12	NM_144687.4	MANE Select	c.193G>C	p.Gly65Arg	missense	Exon 1 of 10	NP_653288.1
NLRP12	NM_001277126.2		c.193G>C	p.Gly65Arg	missense	Exon 1 of 10	NP_001264055.1
NLRP12	NM_001277129.1		c.193G>C	p.Gly65Arg	missense	Exon 1 of 9	NP_001264058.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NLRP12	ENST00000324134.11	TSL:1 MANE Select	c.193G>C	p.Gly65Arg	missense	Exon 1 of 10	ENSP00000319377.6
NLRP12	ENST00000391773.8	TSL:1	c.193G>C	p.Gly65Arg	missense	Exon 1 of 10	ENSP00000375653.1
NLRP12	ENST00000345770.9	TSL:1	c.193G>C	p.Gly65Arg	missense	Exon 1 of 9	ENSP00000341428.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial cold autoinflammatory syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.0077

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.082

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.044

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.70

M_CAP

Benign

0.0092

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

-0.26

MutationAssessor

Pathogenic

3.0

PhyloP100

2.9

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.40

Sift

Uncertain

0.024

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.53

MutPred

0.67

Gain of MoRF binding (P = 0.0585)

MVP

0.62

MPC

0.38

ClinPred

0.94

GERP RS

4.7

PromoterAI

0.27

Neutral

(source)

Varity_R

0.76

gMVP

0.51

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

19-53823982-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over