19-53804068-G-A

Position:

• chr19-53804068-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000324134.11(NLRP12):​c.2469C>T​(p.Leu823=) 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 ENST00000324134.11 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.00600

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]

ACMG classification

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/exons	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.2469C>T	p.Leu823=	synonymous_variant	6/10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.2469C>T	p.Leu823=	synonymous_variant	6/10	1	NM_144687.4	ENSP00000319377	P4

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70669 AN: 151808 Hom.: 18602 Cov.: 31

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

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

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

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

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Familial cold autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Other links and lift over

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