19-53804068-G-T

Position:

• chr19-53804068-G-T

Variant summary

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

The NM_144687.4(NLRP12):​c.2469C>A​(p.Leu823Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0827 in 1,613,674 control chromosomes in the GnomAD database, including 6,215 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 0.061 (399 hom., cov: 31)
  • Exomes 𝑓: 0.085 (5816 hom.)
• Consequence: NLRP12 NM_144687.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• 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=-0.81).
• BP6: Variant 19-53804068-G-T is Benign according to our data. Variant chr19-53804068-G-T is described in ClinVar as [Benign]. Clinvar id is 262530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-53804068-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.006 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.2469C>A	p.Leu823Leu	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>A	p.Leu823Leu	synonymous_variant	6/10	1	NM_144687.4	ENSP00000319377.6
NLRP12	ENST00000345770.9	c.2472C>A	p.Leu824Leu	synonymous_variant	6/9	1		ENSP00000341428.5
NLRP12	ENST00000391772.1	c.2472C>A	p.Leu824Leu	synonymous_variant	6/7	1		ENSP00000375652.1

Frequencies

GnomAD3 genomes AF: 0.0611 AC: 9283 AN: 151850 Hom.: 397 Cov.: 31

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.0492

Gnomad ASJ AF: 0.0666

Gnomad EAS AF: 0.000969

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0932

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0879

Gnomad OTH AF: 0.0531

GnomAD3 exomes AF: 0.0736 AC: 18480 AN: 251008 Hom.: 896 AF XY: 0.0780 AC XY: 10588 AN XY: 135714

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.0612

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.122

Gnomad FIN exome AF: 0.0943

Gnomad NFE exome AF: 0.0905

Gnomad OTH exome AF: 0.0773

GnomAD4 exome AF: 0.0849 AC: 124095 AN: 1461704 Hom.: 5816 Cov.: 48 AF XY: 0.0863 AC XY: 62765 AN XY: 727154

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.0337

Gnomad4 ASJ exome AF: 0.0621

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.0988

Gnomad4 NFE exome AF: 0.0892

Gnomad4 OTH exome AF: 0.0796

GnomAD4 genome AF: 0.0611 AC: 9290 AN: 151970 Hom.: 399 Cov.: 31 AF XY: 0.0615 AC XY: 4563 AN XY: 74236

Gnomad4 AFR AF: 0.0142

Gnomad4 AMR AF: 0.0491

Gnomad4 ASJ AF: 0.0666

Gnomad4 EAS AF: 0.000971

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.0932

Gnomad4 NFE AF: 0.0879

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0388 Hom.: 4657

EpiCase AF: 0.0859

EpiControl AF: 0.0837

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

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 -

Familial cold autoinflammatory syndrome 2 Benign:2

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

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

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	-0.81
CADD	Benign	0.43
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;