rs79884502

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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. R859W) has been classified as Uncertain significance.

• 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
• Publications: 1 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 330016.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 = 0.00855 (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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1302 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144687.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	NM_144687.4	MANE Select	c.2576G>A	p.Arg859Gln	missense	Exon 6 of 10	NP_653288.1	P59046-1
	NLRP12	NM_001277126.2		c.2579G>A	p.Arg860Gln	missense	Exon 6 of 10	NP_001264055.1	P59046-7
	NLRP12	NM_001277129.1		c.2576G>A	p.Arg859Gln	missense	Exon 6 of 9	NP_001264058.1	P59046-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	ENST00000324134.11	TSL:1 MANE Select	c.2576G>A	p.Arg859Gln	missense	Exon 6 of 10	ENSP00000319377.6	P59046-1
	NLRP12	ENST00000391773.8	TSL:1	c.2579G>A	p.Arg860Gln	missense	Exon 6 of 10	ENSP00000375653.1	P59046-7
	NLRP12	ENST00000345770.9	TSL:1	c.2579G>A	p.Arg860Gln	missense	Exon 6 of 9	ENSP00000341428.5	A0A0C4DH17

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

GnomAD2 exomes AF: 0.00234 AC: 588 AN: 251362 AF XY: 0.00168

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 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

African (AFR) AF: 0.0280 AC: 936 AN: 33470

American (AMR) AF: 0.00192 AC: 86 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 24 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.000245 AC: 272 AN: 1111924

Other (OTH) AF: 0.00205 AC: 124 AN: 60392

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

African (AFR) AF: 0.0292 AC: 1215 AN: 41554

American (AMR) AF: 0.00308 AC: 47 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68026

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

Alfa AF: 0.00237 Hom.: 10

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Familial cold autoinflammatory syndrome 2 (4)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.80	N
PhyloP100		-0.096
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs79884502; hg19: chr19-54307215;