rs142063194

Positions:

• chr19-53810690-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_144687.4(NLRP12):​c.969T>G​(p.Leu323=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,942 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (9 hom., cov: 31)
  • Exomes 𝑓: 0.011 (135 hom.)
• Consequence: NLRP12 NM_144687.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.77

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=-1.0).
• BP6: Variant 19-53810690-A-C is Benign according to our data. Variant chr19-53810690-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 262533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-53810690-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.008 (1217/152118) while in subpopulation NFE AF= 0.0133 (901/67978). AF 95% confidence interval is 0.0125. There are 9 homozygotes in gnomad4. There are 556 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1217 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.969T>G	p.Leu323=	synonymous_variant	3/10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.969T>G	p.Leu323=	synonymous_variant	3/10	1	NM_144687.4	ENSP00000319377	P4

Frequencies

GnomAD3 genomes AF: 0.00801 AC: 1217 AN: 152000 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00447

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00623

Gnomad FIN AF: 0.00604

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00859 AC: 2159 AN: 251284 Hom.: 21 AF XY: 0.00891 AC XY: 1210 AN XY: 135864

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00494

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00761

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.00946

GnomAD4 exome AF: 0.0109 AC: 15887 AN: 1461824 Hom.: 135 Cov.: 40 AF XY: 0.0110 AC XY: 7972 AN XY: 727218

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00479

Gnomad4 ASJ exome AF: 0.0161

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00825

Gnomad4 FIN exome AF: 0.00453

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.00800 AC: 1217 AN: 152118 Hom.: 9 Cov.: 31 AF XY: 0.00748 AC XY: 556 AN XY: 74378

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.00446

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.00623

Gnomad4 FIN AF: 0.00604

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.0117 Hom.: 5

Bravo AF: 0.00723

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.0102

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Benign:2

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	Oct 20, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NLRP12: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Likely 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	-1.0
CADD	Benign	0.58
DANN	Benign	0.40

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: rs142063194; hg19: chr19-54313944;