rs61741349

chr19-53801228-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144687.4(NLRP12):c.2755C>T(p.Arg919Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,613,682 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R919Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0065 (17 hom., cov: 30)
  • Exomes 𝑓: 0.00074 (12 hom.)
• Consequence: NLRP12 NM_144687.4 missense, splice_region
• Scores: Splicing: ADA: 0.00003798
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0430

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 (MetaRNN=0.013561815).
• BP6: Variant 19-53801228-G-A is Benign according to our data. Variant chr19-53801228-G-A is described in ClinVar as [Benign]. Clinvar id is 330010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-53801228-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00649 (987/152032) while in subpopulation AFR AF= 0.0219 (908/41494). AF 95% confidence interval is 0.0207. There are 17 homozygotes in gnomad4. There are 486 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 985 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP12	NM_144687.4	c.2755C>T	p.Arg919Trp	missense_variant, splice_region_variant	7/10	ENST00000324134.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP12	ENST00000324134.11	c.2755C>T	p.Arg919Trp	missense_variant, splice_region_variant	7/10	1	NM_144687.4	P4

Frequencies

GnomAD3 genomes AF: 0.00648 AC: 985 AN: 151914 Hom.: 18 Cov.: 30

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00303

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00624

GnomAD3 exomes AF: 0.00172 AC: 430 AN: 250276 Hom.: 5 AF XY: 0.00117 AC XY: 159 AN XY: 135398

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000738 AC: 1079 AN: 1461650 Hom.: 12 Cov.: 35 AF XY: 0.000634 AC XY: 461 AN XY: 727118

Gnomad4 AFR exome AF: 0.0233

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000169

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00649 AC: 987 AN: 152032 Hom.: 17 Cov.: 30 AF XY: 0.00654 AC XY: 486 AN XY: 74296

Gnomad4 AFR AF: 0.0219

Gnomad4 AMR AF: 0.00302

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00618

Alfa AF: 0.00114 Hom.: 2

Bravo AF: 0.00713

ESP6500AA AF: 0.0216 AC: 95

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00210 AC: 255

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 15, 2017	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 21, 2023	- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.67	T;T;T;T
MetaRNN	Benign	0.0089	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L;L;.;.
MutationTaster	Benign	1.0	D;D;D;N;N;N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	D;N;N;D
REVEL	Benign	0.18
Sift	Benign	0.076	T;T;T;T
Sift4G	Uncertain	0.017	D;T;D;T
Polyphen		1.0	D;.;.;.
Vest4		0.40
MVP		0.73
MPC		0.36
ClinPred		0.028	T
GERP RS		-0.83
Varity_R		0.12
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.040
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: rs61741349; hg19: chr19-54304482;