NM_144687.4:c.2171C>T

Variant names:

• chr19-53807567-G-A
• rs201136106
• NM_144687.4:c.2171C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS2

The NM_144687.4(NLRP12):​c.2171C>T​(p.Ala724Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A724A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NLRP12 NM_144687.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.189
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.2171C>T	p.Ala724Val	missense_variant	Exon 4 of 10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.2171C>T	p.Ala724Val	missense_variant	Exon 4 of 10	1	NM_144687.4	ENSP00000319377.6
NLRP12	ENST00000345770.9	c.2174C>T	p.Ala725Val	missense_variant	Exon 4 of 9	1		ENSP00000341428.5
NLRP12	ENST00000391772.1	c.2174C>T	p.Ala725Val	missense_variant	Exon 4 of 7	1		ENSP00000375652.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251376 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111998

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

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

Jun 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 569082). This variant has not been reported in the literature in individuals affected with NLRP12-related conditions. This variant is present in population databases (rs201136106, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 724 of the NLRP12 protein (p.Ala724Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.059	T;.;.;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.46	T;T;T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.45	T;T;T;T;T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.4	L;L;.;.;.
PhyloP100		-0.19
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.0	N;N;N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.53	T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T
Polyphen		0.95	P;.;.;.;.
Vest4		0.44
MutPred		0.32		Loss of MoRF binding (P = 0.1441);Loss of MoRF binding (P = 0.1441);.;.;.;
MVP		0.91
MPC		0.26
ClinPred		0.32	T
GERP RS		2.8
Varity_R		0.082
gMVP		0.10
Mutation Taster		=88/12	polymorphism

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: rs201136106; hg19: chr19-54310821;