rs76085152

chr19-53810307-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144687.4(NLRP12):c.1352G>A(p.Arg451His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,613,804 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R451C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: NLRP12 NM_144687.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.951

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006780505).
• BP6: Variant 19-53810307-C-T is Benign according to our data. Variant chr19-53810307-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 536945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0018 (274/152190) while in subpopulation AFR AF= 0.00626 (260/41532). AF 95% confidence interval is 0.00564. There are 2 homozygotes in gnomad4. There are 121 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 265 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP12	NM_144687.4	c.1352G>A	p.Arg451His	missense_variant	3/10	ENST00000324134.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP12	ENST00000324134.11	c.1352G>A	p.Arg451His	missense_variant	3/10	1	NM_144687.4	P4

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 265 AN: 152072 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00606

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000515 AC: 129 AN: 250642 Hom.: 0 AF XY: 0.000369 AC XY: 50 AN XY: 135628

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000250 AC: 366 AN: 1461614 Hom.: 1 Cov.: 40 AF XY: 0.000241 AC XY: 175 AN XY: 727100

Gnomad4 AFR exome AF: 0.00762

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.00180 AC: 274 AN: 152190 Hom.: 2 Cov.: 32 AF XY: 0.00163 AC XY: 121 AN XY: 74400

Gnomad4 AFR AF: 0.00626

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000694 Hom.: 0

Bravo AF: 0.00224

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000675 AC: 82

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

NLRP12: BP4, BS1 -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	9.4
Dann	Benign	0.96
DEOGEN2	Benign	0.061	T;.;.;.;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.46	T;T;T;T;T
MetaRNN	Benign	0.0068	T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.84	L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.30	N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.098	T;T;T;T;T
Sift4G	Benign	0.10	T;T;T;T;T
Polyphen		0.98	D;.;.;.;.
Vest4		0.10
MVP		0.79
MPC		0.10
ClinPred		0.0056	T
GERP RS		-1.4
Varity_R		0.020
gMVP		0.14

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: rs76085152; hg19: chr19-54313561; COSMIC: COSV60743639; COSMIC: COSV60743639;