chr19-53824059-C-A

Variant names:

• chr19-53824059-C-A
• rs34436714
• NM_144687.4:c.116G>T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:8 O:1
• Conservation: PhyloP100: 1.53
• Publications: 36 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: Benign. The variant received -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 VariationId is 262528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.116G>T	p.Gly39Val	missense_variant	Exon 1 of 10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.116G>T	p.Gly39Val	missense_variant	Exon 1 of 10	1	NM_144687.4	ENSP00000319377.6
NLRP12	ENST00000345770.9	c.116G>T	p.Gly39Val	missense_variant	Exon 1 of 9	1		ENSP00000341428.5
NLRP12	ENST00000391772.1	c.116G>T	p.Gly39Val	missense_variant	Exon 1 of 7	1		ENSP00000375652.1

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

GnomAD2 exomes AF: 0.224 AC: 56279 AN: 251390 AF XY: 0.219

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 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

African (AFR) AF: 0.370 AC: 12376 AN: 33480

American (AMR) AF: 0.252 AC: 11273 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3299 AN: 26136

East Asian (EAS) AF: 0.144 AC: 5713 AN: 39700

South Asian (SAS) AF: 0.247 AC: 21337 AN: 86258

European-Finnish (FIN) AF: 0.195 AC: 10425 AN: 53418

Middle Eastern (MID) AF: 0.156 AC: 902 AN: 5768

European-Non Finnish (NFE) AF: 0.211 AC: 234183 AN: 1111972

Other (OTH) AF: 0.216 AC: 13023 AN: 60394

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

African (AFR) AF: 0.368 AC: 15242 AN: 41458

American (AMR) AF: 0.234 AC: 3580 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 432 AN: 3470

East Asian (EAS) AF: 0.172 AC: 890 AN: 5170

South Asian (SAS) AF: 0.253 AC: 1220 AN: 4814

European-Finnish (FIN) AF: 0.190 AC: 2007 AN: 10590

Middle Eastern (MID) AF: 0.168 AC: 49 AN: 292

European-Non Finnish (NFE) AF: 0.210 AC: 14294 AN: 67970

Other (OTH) AF: 0.217 AC: 457 AN: 2110

Alfa AF: 0.214 Hom.: 7176

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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial cold autoinflammatory syndrome 2 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cold autoinflammatory syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.;.
PhyloP100		1.5
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
PromoterAI		-0.011	Neutral
Varity_R		0.38
gMVP		0.53
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34436714; hg19: chr19-54327313; COSMIC: COSV60747657;