rs145156267

Variant names:

• chr19-53811123-G-A
• rs145156267
• NM_144687.4:c.536C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_144687.4(NLRP12):​c.536C>T​(p.Thr179Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: NLRP12 NM_144687.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -0.688
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034659058).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000251 (367/1461876) while in subpopulation NFE AF = 0.000308 (342/1112010). AF 95% confidence interval is 0.000281. There are 0 homozygotes in GnomAdExome4. There are 172 alleles in the male GnomAdExome4 subpopulation. Median coverage is 40. This position passed quality control check.
• BS2: High AC in GnomAd4 at 21 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.536C>T	p.Thr179Ile	missense	Exon 3 of 10	NP_653288.1	P59046-1
	NLRP12	NM_001277126.2		c.536C>T	p.Thr179Ile	missense	Exon 3 of 10	NP_001264055.1	P59046-7
	NLRP12	NM_001277129.1		c.536C>T	p.Thr179Ile	missense	Exon 3 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.536C>T	p.Thr179Ile	missense	Exon 3 of 10	ENSP00000319377.6	P59046-1
	NLRP12	ENST00000391773.8	TSL:1	c.536C>T	p.Thr179Ile	missense	Exon 3 of 10	ENSP00000375653.1	P59046-7
	NLRP12	ENST00000345770.9	TSL:1	c.536C>T	p.Thr179Ile	missense	Exon 3 of 9	ENSP00000341428.5	A0A0C4DH17

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000955 AC: 24 AN: 251388 AF XY: 0.0000883

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000251 AC: 367 AN: 1461876 Hom.: 0 Cov.: 40 AF XY: 0.000237 AC XY: 172 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000308 AC: 342 AN: 1112010

Other (OTH) AF: 0.000414 AC: 25 AN: 60396

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74274

African (AFR) AF: 0.0000241 AC: 1 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000211 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000600

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.012
DANN	Benign	0.076
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.69
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.85	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.15	B
Vest4		0.066
MVP		0.55
MPC		0.057
ClinPred		0.025	T
GERP RS		-2.4
Varity_R		0.021
gMVP		0.20
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs145156267; hg19: chr19-54314377;