rs111234757

Positions:

• chr19-53810312-G-C

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.1347C>G​(p.Ala449Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,613,762 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (84 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (91 hom.)
• Consequence: NLRP12 NM_144687.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.778

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=-0.85).
• BP6: Variant 19-53810312-G-C is Benign according to our data. Variant chr19-53810312-G-C is described in ClinVar as [Benign]. Clinvar id is 330032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-53810312-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.778 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.1347C>G	p.Ala449Ala	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.1347C>G	p.Ala449Ala	synonymous_variant	3/10	1	NM_144687.4	ENSP00000319377.6
NLRP12	ENST00000345770.9	c.1347C>G	p.Ala449Ala	synonymous_variant	3/9	1		ENSP00000341428.5
NLRP12	ENST00000391772.1	c.1347C>G	p.Ala449Ala	synonymous_variant	3/7	1		ENSP00000375652.1

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3024 AN: 152096 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.0637

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00669 AC: 1675 AN: 250556 Hom.: 55 AF XY: 0.00524 AC XY: 710 AN XY: 135610

Gnomad AFR exome AF: 0.0668

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.0333

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000768

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00297 AC: 4335 AN: 1461548 Hom.: 91 Cov.: 40 AF XY: 0.00277 AC XY: 2014 AN XY: 727074

Gnomad4 AFR exome AF: 0.0651

Gnomad4 AMR exome AF: 0.00508

Gnomad4 ASJ exome AF: 0.0324

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000531

Gnomad4 OTH exome AF: 0.00735

GnomAD4 genome AF: 0.0199 AC: 3030 AN: 152214 Hom.: 84 Cov.: 32 AF XY: 0.0190 AC XY: 1417 AN XY: 74402

Gnomad4 AFR AF: 0.0637

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.0346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.0165

Alfa AF: 0.00962 Hom.: 10

Bravo AF: 0.0236

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.63
DANN	Benign	0.39

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: rs111234757; hg19: chr19-54313566;