19-53823982-C-G

Variant names:

• chr19-53823982-C-G
• rs376902606
• NM_144687.4:c.193G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_144687.4(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_144687.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.90
• Publications: 0 publications found

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

ACMG classification

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.193G>C	p.Gly65Arg	missense_variant	Exon 1 of 10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.193G>C	p.Gly65Arg	missense_variant	Exon 1 of 10	1	NM_144687.4	ENSP00000319377.6
NLRP12	ENST00000345770.9	c.193G>C	p.Gly65Arg	missense_variant	Exon 1 of 9	1		ENSP00000341428.5
NLRP12	ENST00000391772.1	c.193G>C	p.Gly65Arg	missense_variant	Exon 1 of 7	1		ENSP00000375652.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Uncertain:1

Jul 13, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with NLRP12-related disease. This sequence change replaces glycine with arginine at codon 65 of the NLRP12 protein (p.Gly65Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.0077	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T;.;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.044
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.70	T;T;T;T;T
M_CAP	Benign	0.0092	T
MetaRNN	Pathogenic	0.83	D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.0	M;M;M;.;.
PhyloP100		2.9
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.024	D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.53
MutPred		0.67		Gain of MoRF binding (P = 0.0585);Gain of MoRF binding (P = 0.0585);Gain of MoRF binding (P = 0.0585);Gain of MoRF binding (P = 0.0585);Gain of MoRF binding (P = 0.0585);
MVP		0.62
MPC		0.38
ClinPred		0.94	D
GERP RS		4.7
PromoterAI		0.27	Neutral
Varity_R		0.76
gMVP		0.51
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs376902606; hg19: chr19-54327236;