19-53810453-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:2

Conservation

PhyloP100: -3.39

Publications

44 publications found

Variant links:

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

NLRP12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

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

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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0649

AC XY:

47219

AN XY:

727210

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

6191

12383

18574

24766

30957

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3012

6024

9036

12048

15060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0505

AC:

7688

AN:

152246

Hom.:

296

Cov.:

AF XY:

0.0492

AC XY:

3665

AN XY:

74442

show subpopulations

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:

AN:

5172

South Asian (SAS)

AF:

0.0197

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0512

AC:

544

AN:

10616

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0784

AC:

5333

AN:

68002

Other (OTH)

AF:

0.0469

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

362

724

1087

1449

1811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0557

Hom.:

Bravo

AF:

0.0483

TwinsUK

AF:

0.0744

AC:

276

ALSPAC

AF:

0.0854

AC:

329

ESP6500AA

AF:

0.0127

AC:

ESP6500EA

AF:

0.0708

AC:

609

ExAC

AF:

0.0519

AC:

6301

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.0797

EpiControl

AF:

0.0833

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial cold autoinflammatory syndrome 2 (2)

Autoinflammatory syndrome (1)

Familial cold autoinflammatory syndrome (1)

not provided (2)

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

BayesDel_noAF

Benign

-0.29

CADD

Benign

8.8

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.16

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.021

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0038

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.5

PhyloP100

-3.4

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.37

Sift

Benign

0.082

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.097

MutPred

0.33

Loss of helix (P = 0.0558)

MPC

0.37

ClinPred

0.072

GERP RS

-6.7

Varity_R

0.19

gMVP

0.22

Mutation Taster

=88/12

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over