19-53810453-G-C

Position:

chr19-53810453-G-C

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 262529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-53810453-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP12	NM_144687.4 linkuse as main transcript	c.1206C>G	p.Phe402Leu	missense_variant	3/10	ENST00000324134.11	NP_653288.1	P59046-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NLRP12	ENST00000324134.11 linkuse as main transcript	c.1206C>G	p.Phe402Leu	missense_variant	3/10	1	NM_144687.4	ENSP00000319377.6	P59046-1
NLRP12	ENST00000345770.9 linkuse as main transcript	c.1206C>G	p.Phe402Leu	missense_variant	3/9	1		ENSP00000341428.5	A0A0C4DH17
NLRP12	ENST00000391772.1 linkuse as main transcript	c.1206C>G	p.Phe402Leu	missense_variant	3/7	1		ENSP00000375652.1	A0A0C4DFY3

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

GnomAD3 exomes

AF:

0.0508

AC:

12766

AN:

251396

Hom.:

448

AF XY:

0.0514

AC XY:

6982

AN XY:

135882

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 SAS exome

AF:

0.0192

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

Gnomad4 AFR exome

AF:

0.0103

Gnomad4 AMR exome

AF:

0.0356

Gnomad4 ASJ exome

AF:

0.0386

Gnomad4 EAS exome

AF:

0.0138

Gnomad4 SAS exome

AF:

0.0203

Gnomad4 FIN exome

AF:

0.0530

Gnomad4 NFE exome

AF:

0.0768

Gnomad4 OTH exome

AF:

0.0566

GnomAD4 genome

AF:

0.0505

AC:

7688

AN:

152246

Hom.:

296

Cov.:

AF XY:

0.0492

AC XY:

3665

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0133

Gnomad4 AMR

AF:

0.0539

Gnomad4 ASJ

AF:

0.0375

Gnomad4 EAS

AF:

0.00947

Gnomad4 SAS

AF:

0.0197

Gnomad4 FIN

AF:

0.0512

Gnomad4 NFE

AF:

0.0784

Gnomad4 OTH

AF:

0.0469

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

Significance: Benign

Submissions summary: Benign:6Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cold autoinflammatory syndrome 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:1Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 14, 2022

- -

Familial cold autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

FAMILIAL COLD AUTOINFLAMMATORY SYNDROME 2, SUSCEPTIBILITY TO

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.41

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

LIST_S2

Uncertain

0.89

D;D;D;D;D

MetaRNN

Benign

0.0038

T;T;T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.5

L;L;L;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.9

D;D;D;D;D

REVEL

Uncertain

0.37

Sift

Benign

0.082

T;T;T;T;T

Sift4G

Benign

0.14

T;T;T;T;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.097

MutPred

0.33

Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);

MPC

0.37

ClinPred

0.072

GERP RS

-6.7

Varity_R

0.19

gMVP

0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over