chr19-53809587-A-T

Variant names:

• chr19-53809587-A-T
• rs760012636
• NM_144687.4:c.2072T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144687.4(NLRP12):​c.2072T>A​(p.Leu691Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 18/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L691P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP12 NM_144687.4 missense, splice_region
• Scores: Splicing: ADA: 0.00001883
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.96
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.098255694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.2072T>A	p.Leu691Gln	missense_variant, splice_region_variant	Exon 3 of 10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.2072T>A	p.Leu691Gln	missense_variant, splice_region_variant	Exon 3 of 10	1	NM_144687.4	ENSP00000319377.6
NLRP12	ENST00000345770.9	c.2072T>A	p.Leu691His	missense_variant, splice_region_variant	Exon 3 of 9	1		ENSP00000341428.5
NLRP12	ENST00000391772.1	c.2072T>A	p.Leu691His	missense_variant, splice_region_variant	Exon 3 of 7	1		ENSP00000375652.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Uncertain:1

Sep 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with NLRP12-related conditions. This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 691 of the NLRP12 protein (p.Leu691Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.64
DANN	Benign	0.75
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.28	T;T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.098	T;T;T
MetaSVM	Benign	-0.87	T
PhyloP100		-3.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.4	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.53	T;T;T
Vest4		0.15
MutPred		0.54		Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);
MVP		0.48
ClinPred		0.072	T
GERP RS		-2.3
Varity_R		0.070
gMVP		0.26
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0020
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: rs760012636; hg19: chr19-54312841;