rs199881207

chr19-53810605-G-Achr19-53810605-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_144687.4(NLRP12):c.1054C>T(p.Arg352Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,614,044 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R352H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: NLRP12 NM_144687.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:4
• Conservation: PhyloP100: 0.559

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1699152).
• BP6: Variant 19-53810605-G-A is Benign according to our data. Variant chr19-53810605-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 523654.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.
• BS2: High AC in GnomAd at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP12	NM_144687.4	c.1054C>T	p.Arg352Cys	missense_variant	3/10	ENST00000324134.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP12	ENST00000324134.11	c.1054C>T	p.Arg352Cys	missense_variant	3/10	1	NM_144687.4	P4

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000378 AC: 95 AN: 251250 Hom.: 0 AF XY: 0.000479 AC XY: 65 AN XY: 135816

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000287 AC: 419 AN: 1461852 Hom.: 1 Cov.: 40 AF XY: 0.000326 AC XY: 237 AN XY: 727222

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000985

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000264

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74418

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000325 Hom.: 0

Bravo AF: 0.000204

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Pathogenic:1 Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2019	The NLRP12 c.1054C>T; p.Arg352Cys variant (rs199881207) is published in the medical literature in 3 unrelated individuals with periodic fever or autoimmune disease without urticaria (Jeru 2011, Rusmini 2016). The variant is reported in the ClinVar database (Variation ID: 523654) and in the general population with an allele frequency of 0.04% (102/282638 alleles) in the Genome Aggregation Database. The arginine at this position is moderately conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Experiments in cell culture show this variant did not affect the NF-KB inhibitory activity, but did enhance processing of caspase-1 compared to wild type (Jeru 2011); these authors suggested that this variant may act in a gain of function mechanism, in contrast to NLRP12 nonsense variants that appear to have a loss of function. However, given the limited clinical and functional data, the significance of the variant is uncertain at this time. References: Jeru I et al. Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis Rheum. 2011 May;63(5):1459-64. Rusmini M et al. Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases. Ann Rheum Dis. 2016 Aug;75(8):1550-7. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 07, 2022	- -

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NLRP12: BP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.20	T;.;.;.;.
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.17	T;T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.4	L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.039	D;D;D;D;D
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.49
MVP		0.88
MPC		0.37
ClinPred		0.052	T
GERP RS		2.1
Varity_R		0.22
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs199881207; hg19: chr19-54313859; COSMIC: COSV60743382; COSMIC: COSV60743382;