NM_144687.4:c.1206C>G

Variant names:

• chr19-53810453-G-C
• rs34971363
• NM_144687.4:c.1206C>G

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.1206C>G​(p.Phe402Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0649 in 1,614,042 control chromosomes in the GnomAD database, including 3,946 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F402F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.050 (296 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3650 hom.)
• Consequence: NLRP12 NM_144687.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:2
• Conservation: PhyloP100: -3.39
• Publications: 44 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=0.0038453639).
• BP6: Variant 19-53810453-G-C is Benign according to our data. Variant chr19-53810453-G-C is described in ClinVar as Benign. ClinVar VariationId is 262529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

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.1206C>G	p.Phe402Leu	missense	Exon 3 of 10	NP_653288.1	P59046-1
	NLRP12	NM_001277126.2		c.1206C>G	p.Phe402Leu	missense	Exon 3 of 10	NP_001264055.1	P59046-7
	NLRP12	NM_001277129.1		c.1206C>G	p.Phe402Leu	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.1206C>G	p.Phe402Leu	missense	Exon 3 of 10	ENSP00000319377.6	P59046-1
	NLRP12	ENST00000391773.8	TSL:1	c.1206C>G	p.Phe402Leu	missense	Exon 3 of 10	ENSP00000375653.1	P59046-7
	NLRP12	ENST00000345770.9	TSL:1	c.1206C>G	p.Phe402Leu	missense	Exon 3 of 9	ENSP00000341428.5	A0A0C4DH17

Frequencies

GnomAD3 genomes AF: 0.0505 AC: 7688 AN: 152126 Hom.: 296 Cov.: 32

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.0441

Gnomad AMR AF: 0.0539

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.00945

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.0512

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.0784

Gnomad OTH AF: 0.0469

GnomAD2 exomes AF: 0.0508 AC: 12766 AN: 251396 AF XY: 0.0514

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.0340

Gnomad ASJ exome AF: 0.0379

Gnomad EAS exome AF: 0.00778

Gnomad FIN exome AF: 0.0516

Gnomad NFE exome AF: 0.0774

Gnomad OTH exome AF: 0.0622

GnomAD4 exome AF: 0.0664 AC: 97094 AN: 1461796 Hom.: 3650 Cov.: 41 AF XY: 0.0649 AC XY: 47219 AN XY: 727210

African (AFR) AF: 0.0103 AC: 346 AN: 33480

American (AMR) AF: 0.0356 AC: 1593 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0386 AC: 1008 AN: 26136

East Asian (EAS) AF: 0.0138 AC: 546 AN: 39700

South Asian (SAS) AF: 0.0203 AC: 1752 AN: 86258

European-Finnish (FIN) AF: 0.0530 AC: 2830 AN: 53346

Middle Eastern (MID) AF: 0.0347 AC: 200 AN: 5768

European-Non Finnish (NFE) AF: 0.0768 AC: 85398 AN: 1111990

Other (OTH) AF: 0.0566 AC: 3421 AN: 60394

GnomAD4 genome AF: 0.0505 AC: 7688 AN: 152246 Hom.: 296 Cov.: 32 AF XY: 0.0492 AC XY: 3665 AN XY: 74442

African (AFR) AF: 0.0133 AC: 552 AN: 41570

American (AMR) AF: 0.0539 AC: 824 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0375 AC: 130 AN: 3468

East Asian (EAS) AF: 0.00947 AC: 49 AN: 5172

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4820

European-Finnish (FIN) AF: 0.0512 AC: 544 AN: 10616

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0784 AC: 5333 AN: 68002

Other (OTH) AF: 0.0469 AC: 99 AN: 2112

Alfa AF: 0.0557 Hom.: 95

Bravo AF: 0.0483

TwinsUK AF: 0.0744 AC: 276

ALSPAC AF: 0.0854 AC: 329

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.0708 AC: 609

ExAC AF: 0.0519 AC: 6301

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.0797

EpiControl AF: 0.0833

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Familial cold autoinflammatory syndrome 2 (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Familial cold autoinflammatory syndrome (1)
-	-	1	not provided (2)
-	-	1	not specified (1)
-	-	-	FAMILIAL COLD AUTOINFLAMMATORY SYNDROME 2, SUSCEPTIBILITY TO (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	8.8
DANN	Benign	0.93
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.021	N
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.5	L
PhyloP100		-3.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.37
Sift	Benign	0.082	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.097
MutPred		0.33		Loss of helix (P = 0.0558)
MPC		0.37
ClinPred		0.072	T
GERP RS		-6.7
Varity_R		0.19
gMVP		0.22
Mutation Taster		=88/12	polymorphism (auto)

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: rs34971363; hg19: chr19-54313707; COSMIC: COSV60744922; COSMIC: COSV60744922;