rs34436714

chr19-53824059-C-Achr19-53824059-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144687.4(NLRP12):c.116G>T(p.Gly39Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 1,613,906 control chromosomes in the GnomAD database, including 39,803 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G39R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.25 (5246 hom., cov: 31)
  • Exomes 𝑓: 0.21 (34557 hom.)
• Consequence: NLRP12 NM_144687.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 1.53

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=0.0028185844).
• BP6: Variant 19-53824059-C-A is Benign according to our data. Variant chr19-53824059-C-A is described in ClinVar as [Benign]. Clinvar id is 262528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-53824059-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP12	NM_144687.4	c.116G>T	p.Gly39Val	missense_variant	1/10	ENST00000324134.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP12	ENST00000324134.11	c.116G>T	p.Gly39Val	missense_variant	1/10	1	NM_144687.4	P4

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38404 AN: 151938 Hom.: 5229 Cov.: 31

Gnomad AFR AF: 0.367

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.218

GnomAD3 exomes AF: 0.224 AC: 56279 AN: 251390 Hom.: 6733 AF XY: 0.219 AC XY: 29759 AN XY: 135870

Gnomad AFR exome AF: 0.373

Gnomad AMR exome AF: 0.253

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.178

Gnomad SAS exome AF: 0.246

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.210

GnomAD4 exome AF: 0.214 AC: 312531 AN: 1461848 Hom.: 34557 Cov.: 35 AF XY: 0.214 AC XY: 155607 AN XY: 727218

Gnomad4 AFR exome AF: 0.370

Gnomad4 AMR exome AF: 0.252

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.144

Gnomad4 SAS exome AF: 0.247

Gnomad4 FIN exome AF: 0.195

Gnomad4 NFE exome AF: 0.211

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.253 AC: 38462 AN: 152058 Hom.: 5246 Cov.: 31 AF XY: 0.251 AC XY: 18640 AN XY: 74336

Gnomad4 AFR AF: 0.368

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.172

Gnomad4 SAS AF: 0.253

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.210

Gnomad4 OTH AF: 0.217

Alfa AF: 0.208 Hom.: 4416

Bravo AF: 0.261

TwinsUK AF: 0.200 AC: 741

ALSPAC AF: 0.219 AC: 843

ESP6500AA AF: 0.367 AC: 1619

ESP6500EA AF: 0.215 AC: 1851

ExAC AF: 0.229 AC: 27843

Asia WGS AF: 0.188 AC: 654 AN: 3478

EpiCase AF: 0.194

EpiControl AF: 0.188

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 49% of patients studied by a panel of primary immunodeficiencies. Number of patients: 47. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Familial cold autoinflammatory syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Familial cold autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	14
Dann	Benign	0.97
DEOGEN2	Benign	0.11	T;.;.;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.59	T;T;T;T;T
MetaRNN	Benign	0.0028	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.8	M;M;M;.;.
MutationTaster	Benign	0.39	P;P;P;P;P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.010	D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D
Polyphen		0.051	B;.;.;.;.
Vest4		0.19
MPC		0.38
ClinPred		0.035	T
GERP RS		4.5
Varity_R		0.38
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34436714; hg19: chr19-54327313; COSMIC: COSV60747657;