rs116129563

Positions:

• chr19-53823868-G-A
• chr19-53823868-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144687.4(NLRP12):​c.289+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00763 in 1,613,452 control chromosomes in the GnomAD database, including 639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (311 hom., cov: 30)
  • Exomes 𝑓: 0.0046 (328 hom.)
• Consequence: NLRP12 NM_144687.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.117

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-53823868-G-A is Benign according to our data. Variant chr19-53823868-G-A is described in ClinVar as [Benign]. Clinvar id is 97904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-53823868-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.289+18C>T		intron_variant		ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.289+18C>T		intron_variant		1	NM_144687.4	ENSP00000319377.6
NLRP12	ENST00000345770.9	c.289+18C>T		intron_variant		1		ENSP00000341428.5
NLRP12	ENST00000391772.1	c.289+18C>T		intron_variant		1		ENSP00000375652.1

Frequencies

GnomAD3 genomes AF: 0.0366 AC: 5554 AN: 151944 Hom.: 311 Cov.: 30

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.0332

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.0364

GnomAD3 exomes AF: 0.0107 AC: 2636 AN: 247222 Hom.: 120 AF XY: 0.00836 AC XY: 1123 AN XY: 134272

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.00709

Gnomad ASJ exome AF: 0.0328

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000843

Gnomad OTH exome AF: 0.00688

GnomAD4 exome AF: 0.00462 AC: 6748 AN: 1461390 Hom.: 328 Cov.: 30 AF XY: 0.00399 AC XY: 2904 AN XY: 726992

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.00881

Gnomad4 ASJ exome AF: 0.0316

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000471

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.0366 AC: 5570 AN: 152062 Hom.: 311 Cov.: 30 AF XY: 0.0361 AC XY: 2683 AN XY: 74350

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.0332

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0177 Hom.: 13

Bravo AF: 0.0425

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2021	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial cold autoinflammatory syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.2
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs116129563; hg19: chr19-54327122;