rs141245482

Variant names:

• chr19-53810749-G-A
• rs141245482
• NM_144687.4:c.910C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_144687.4(NLRP12):​c.910C>T​(p.His304Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 1,614,044 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H304Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0038 (21 hom.)
• Consequence: NLRP12 NM_144687.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 1.18
• Publications: 23 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007107258).
• BP6: Variant 19-53810749-G-A is Benign according to our data. Variant chr19-53810749-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262532.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00377 (574/152192) while in subpopulation NFE AF = 0.00366 (249/68012). AF 95% confidence interval is 0.00329. There are 4 homozygotes in GnomAd4. There are 337 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 574 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.910C>T	p.His304Tyr	missense	Exon 3 of 10	NP_653288.1	P59046-1
	NLRP12	NM_001277126.2		c.910C>T	p.His304Tyr	missense	Exon 3 of 10	NP_001264055.1	P59046-7
	NLRP12	NM_001277129.1		c.910C>T	p.His304Tyr	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.910C>T	p.His304Tyr	missense	Exon 3 of 10	ENSP00000319377.6	P59046-1
	NLRP12	ENST00000391773.8	TSL:1	c.910C>T	p.His304Tyr	missense	Exon 3 of 10	ENSP00000375653.1	P59046-7
	NLRP12	ENST00000345770.9	TSL:1	c.910C>T	p.His304Tyr	missense	Exon 3 of 9	ENSP00000341428.5	A0A0C4DH17

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 574 AN: 152072 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00366

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00432 AC: 1086 AN: 251246 AF XY: 0.00430

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00676

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.00359

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00384 AC: 5619 AN: 1461852 Hom.: 21 Cov.: 40 AF XY: 0.00372 AC XY: 2702 AN XY: 727226

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.00288 AC: 129 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00696 AC: 182 AN: 26136

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

South Asian (SAS) AF: 0.00110 AC: 95 AN: 86258

European-Finnish (FIN) AF: 0.0224 AC: 1195 AN: 53378

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00340 AC: 3778 AN: 1112012

Other (OTH) AF: 0.00356 AC: 215 AN: 60396

GnomAD4 genome AF: 0.00377 AC: 574 AN: 152192 Hom.: 4 Cov.: 31 AF XY: 0.00453 AC XY: 337 AN XY: 74412

African (AFR) AF: 0.000602 AC: 25 AN: 41546

American (AMR) AF: 0.00157 AC: 24 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.0214 AC: 227 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00366 AC: 249 AN: 68012

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00308 Hom.: 1

Bravo AF: 0.00241

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00422 AC: 513

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00427

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	Familial cold autoinflammatory syndrome 2 (6)
-	-	3	not provided (3)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.099
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.42
MVP		0.90
MPC		0.36
ClinPred		0.018	T
GERP RS		3.4
Varity_R		0.52
gMVP		0.20
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141245482; hg19: chr19-54314003; COSMIC: COSV106101752; COSMIC: COSV106101752;