rs143855597

chr19-53810596-C-T

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.1063G>A(p.Glu355Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,614,112 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: NLRP12 NM_144687.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00200

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=0.009685606).
• BP6: Variant 19-53810596-C-T is Benign according to our data. Variant chr19-53810596-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 469088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00145 (221/152264) while in subpopulation AFR AF= 0.00493 (205/41558). AF 95% confidence interval is 0.00438. There are 0 homozygotes in gnomad4. There are 108 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 221 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP12	NM_144687.4	c.1063G>A	p.Glu355Lys	missense_variant	3/10	ENST00000324134.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP12	ENST00000324134.11	c.1063G>A	p.Glu355Lys	missense_variant	3/10	1	NM_144687.4	P4

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00495

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000338 AC: 85 AN: 251316 Hom.: 0 AF XY: 0.000272 AC XY: 37 AN XY: 135836

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 224 AN: 1461848 Hom.: 1 Cov.: 40 AF XY: 0.000135 AC XY: 98 AN XY: 727218

Gnomad4 AFR exome AF: 0.00529

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74436

Gnomad4 AFR AF: 0.00493

Gnomad4 AMR AF: 0.000917

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000449 Hom.: 2

Bravo AF: 0.00196

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000436 AC: 53

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	- -

NLRP12-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 26, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.075	T;.;.;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.59	T;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0097	T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.81	L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.58	N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.56	T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.17
MVP		0.90
MPC		0.33
ClinPred		0.025	T
GERP RS		2.1
Varity_R		0.049
gMVP		0.28

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: rs143855597; hg19: chr19-54313850;