rs79884502

Variant names:

• chr19-53803961-C-T
• rs79884502
• NM_144687.4:c.2576G>A

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.2576G>A​(p.Arg859Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,614,016 control chromosomes in the GnomAD database, including 22 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (9 hom.)
• Consequence: NLRP12 NM_144687.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0960

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=0.00214836).
• BP6: Variant 19-53803961-C-T is Benign according to our data. Variant chr19-53803961-C-T is described in ClinVar as [Benign]. Clinvar id is 330016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-53803961-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00855 (1302/152240) while in subpopulation AFR AF= 0.0292 (1215/41554). AF 95% confidence interval is 0.0279. There are 13 homozygotes in gnomad4. There are 609 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1302 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.2576G>A	p.Arg859Gln	missense_variant	Exon 6 of 10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.2576G>A	p.Arg859Gln	missense_variant	Exon 6 of 10	1	NM_144687.4	ENSP00000319377.6
NLRP12	ENST00000345770.9	c.2579G>A	p.Arg860Gln	missense_variant	Exon 6 of 9	1		ENSP00000341428.5
NLRP12	ENST00000391772.1	c.2579G>A	p.Arg860Gln	missense_variant	Exon 6 of 7	1		ENSP00000375652.1

Frequencies

GnomAD3 genomes AF: 0.00858 AC: 1305 AN: 152122 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00234 AC: 588 AN: 251362 Hom.: 4 AF XY: 0.00168 AC XY: 228 AN XY: 135892

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00100 AC: 1468 AN: 1461776 Hom.: 9 Cov.: 30 AF XY: 0.000903 AC XY: 657 AN XY: 727198

Gnomad4 AFR exome AF: 0.0280

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000245

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.00855 AC: 1302 AN: 152240 Hom.: 13 Cov.: 33 AF XY: 0.00818 AC XY: 609 AN XY: 74432

Gnomad4 AFR AF: 0.0292

Gnomad4 AMR AF: 0.00308

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00180 Hom.: 8

Bravo AF: 0.00958

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0293 AC: 129

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00306 AC: 371

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Benign:4

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 16, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autoinflammatory syndrome Benign:1

Feb 25, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

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	0.060
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.017
DANN	Benign	0.36
DEOGEN2	Benign	0.057	T;.;.;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00081	N
LIST_S2	Benign	0.41	T;T;T;T;T
MetaRNN	Benign	0.0021	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.80	N;N;.;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.2	N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.052
MVP		0.30
MPC		0.059
ClinPred		0.00032	T
GERP RS		-7.3
Varity_R		0.015
gMVP		0.096

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs79884502; hg19: chr19-54307215;