NM_144687.4:c.2469C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_144687.4(NLRP12):​c.2469C>T​(p.Leu823Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.552 in 1,613,480 control chromosomes in the GnomAD database, including 253,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L823L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.47 ( 18607 hom., cov: 31)
Exomes 𝑓: 0.56 ( 234809 hom. )

Consequence

NLRP12
NM_144687.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.00600
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 19-53804068-G-A is Benign according to our data. Variant chr19-53804068-G-A is described in ClinVar as [Benign]. Clinvar id is 262531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-53804068-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.006 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NLRP12NM_144687.4 linkc.2469C>T p.Leu823Leu synonymous_variant Exon 6 of 10 ENST00000324134.11 NP_653288.1 P59046-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NLRP12ENST00000324134.11 linkc.2469C>T p.Leu823Leu synonymous_variant Exon 6 of 10 1 NM_144687.4 ENSP00000319377.6 P59046-1
NLRP12ENST00000345770.9 linkc.2472C>T p.Leu824Leu synonymous_variant Exon 6 of 9 1 ENSP00000341428.5 A0A0C4DH17
NLRP12ENST00000391772.1 linkc.2472C>T p.Leu824Leu synonymous_variant Exon 6 of 7 1 ENSP00000375652.1 A0A0C4DFY3

Frequencies

GnomAD3 genomes
AF:
0.466
AC:
70669
AN:
151808
Hom.:
18602
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.199
Gnomad AMI
AF:
0.660
Gnomad AMR
AF:
0.544
Gnomad ASJ
AF:
0.584
Gnomad EAS
AF:
0.574
Gnomad SAS
AF:
0.409
Gnomad FIN
AF:
0.595
Gnomad MID
AF:
0.443
Gnomad NFE
AF:
0.576
Gnomad OTH
AF:
0.508
GnomAD3 exomes
AF:
0.530
AC:
133138
AN:
251008
Hom.:
36924
AF XY:
0.531
AC XY:
72112
AN XY:
135714
show subpopulations
Gnomad AFR exome
AF:
0.193
Gnomad AMR exome
AF:
0.558
Gnomad ASJ exome
AF:
0.584
Gnomad EAS exome
AF:
0.576
Gnomad SAS exome
AF:
0.408
Gnomad FIN exome
AF:
0.591
Gnomad NFE exome
AF:
0.579
Gnomad OTH exome
AF:
0.546
GnomAD4 exome
AF:
0.561
AC:
820227
AN:
1461552
Hom.:
234809
Cov.:
48
AF XY:
0.558
AC XY:
405557
AN XY:
727106
show subpopulations
Gnomad4 AFR exome
AF:
0.183
Gnomad4 AMR exome
AF:
0.557
Gnomad4 ASJ exome
AF:
0.582
Gnomad4 EAS exome
AF:
0.525
Gnomad4 SAS exome
AF:
0.410
Gnomad4 FIN exome
AF:
0.589
Gnomad4 NFE exome
AF:
0.585
Gnomad4 OTH exome
AF:
0.541
GnomAD4 genome
AF:
0.465
AC:
70680
AN:
151928
Hom.:
18607
Cov.:
31
AF XY:
0.469
AC XY:
34777
AN XY:
74228
show subpopulations
Gnomad4 AFR
AF:
0.199
Gnomad4 AMR
AF:
0.544
Gnomad4 ASJ
AF:
0.584
Gnomad4 EAS
AF:
0.574
Gnomad4 SAS
AF:
0.409
Gnomad4 FIN
AF:
0.595
Gnomad4 NFE
AF:
0.576
Gnomad4 OTH
AF:
0.505
Alfa
AF:
0.539
Hom.:
4657
EpiCase
AF:
0.563
EpiControl
AF:
0.570

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Mar 29, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 12, 2023
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 81% of patients studied by a panel of primary immunodeficiencies. Number of patients: 78. Only high quality variants are reported. -

Familial cold autoinflammatory syndrome 2 Benign:3
Sep 05, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 26, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Familial cold autoinflammatory syndrome Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.80
CADD
Benign
1.1
DANN
Benign
0.56

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.

Other links and lift over

dbSNP: rs12460528; hg19: chr19-54307322; COSMIC: COSV60743403; API