19-53810699-C-T

Position:

• chr19-53810699-C-T

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.960G>A​(p.Thr320=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00485 in 1,613,950 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (33 hom.)
• Consequence: NLRP12 NM_144687.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.16

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=-0.67).
• BP6: Variant 19-53810699-C-T is Benign according to our data. Variant chr19-53810699-C-T is described in ClinVar as [Benign]. Clinvar id is 330034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00304 (462/152110) while in subpopulation NFE AF= 0.0049 (333/68008). AF 95% confidence interval is 0.00446. There are 0 homozygotes in gnomad4. There are 200 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 462 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP12	NM_144687.4	c.960G>A	p.Thr320=	synonymous_variant	3/10	ENST00000324134.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP12	ENST00000324134.11	c.960G>A	p.Thr320=	synonymous_variant	3/10	1	NM_144687.4	P4

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 462 AN: 151992 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000986

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00462

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00490

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00377 AC: 948 AN: 251262 Hom.: 3 AF XY: 0.00386 AC XY: 525 AN XY: 135854

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.00504

Gnomad NFE exome AF: 0.00591

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00504 AC: 7371 AN: 1461840 Hom.: 33 Cov.: 40 AF XY: 0.00506 AC XY: 3677 AN XY: 727224

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00268

Gnomad4 FIN exome AF: 0.00470

Gnomad4 NFE exome AF: 0.00584

Gnomad4 OTH exome AF: 0.00394

GnomAD4 genome AF: 0.00304 AC: 462 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.00269 AC XY: 200 AN XY: 74360

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.000984

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00462

Gnomad4 NFE AF: 0.00490

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00472 Hom.: 3

Bravo AF: 0.00305

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 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 03, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

NLRP12: BP4, BP7, BS1, BS2 -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.053
DANN	Benign	0.43

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: rs77625808; hg19: chr19-54313953;