rs12460528

Variant names:

• chr19-53804068-G-A
• rs12460528
• NM_144687.4:c.2469C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-53804068-G-A
• chr19-53804068-G-T
• chr19-53804068-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_144687.4(NLRP12):​c.2469C>T​(p.Leu823Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.552 in 1,613,480 control chromosomes in the GnomAD database, including 253,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L823L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.47 (18607 hom., cov: 31)
  • Exomes 𝑓: 0.56 (234809 hom.)
• Consequence: NLRP12 NM_144687.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.00600
• Publications: 18 publications found

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]

NLRP12 Gene-Disease associations (from GenCC):

• familial cold autoinflammatory syndrome 2

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-53804068-G-A is Benign according to our data. Variant chr19-53804068-G-A is described in ClinVar as Benign. ClinVar VariationId is 262531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.006 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144687.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	NM_144687.4	MANE Select	c.2469C>T	p.Leu823Leu	synonymous	Exon 6 of 10	NP_653288.1	P59046-1
	NLRP12	NM_001277126.2		c.2472C>T	p.Leu824Leu	synonymous	Exon 6 of 10	NP_001264055.1	P59046-7
	NLRP12	NM_001277129.1		c.2469C>T	p.Leu823Leu	synonymous	Exon 6 of 9	NP_001264058.1	P59046-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	ENST00000324134.11	TSL:1 MANE Select	c.2469C>T	p.Leu823Leu	synonymous	Exon 6 of 10	ENSP00000319377.6	P59046-1
	NLRP12	ENST00000391773.8	TSL:1	c.2472C>T	p.Leu824Leu	synonymous	Exon 6 of 10	ENSP00000375653.1	P59046-7
	NLRP12	ENST00000345770.9	TSL:1	c.2472C>T	p.Leu824Leu	synonymous	Exon 6 of 9	ENSP00000341428.5	A0A0C4DH17

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70669 AN: 151808 Hom.: 18602 Cov.: 31

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.660

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.574

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.595

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.508

GnomAD2 exomes AF: 0.530 AC: 133138 AN: 251008 AF XY: 0.531

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.558

Gnomad ASJ exome AF: 0.584

Gnomad EAS exome AF: 0.576

Gnomad FIN exome AF: 0.591

Gnomad NFE exome AF: 0.579

Gnomad OTH exome AF: 0.546

GnomAD4 exome AF: 0.561 AC: 820227 AN: 1461552 Hom.: 234809 Cov.: 48 AF XY: 0.558 AC XY: 405557 AN XY: 727106

African (AFR) AF: 0.183 AC: 6132 AN: 33478

American (AMR) AF: 0.557 AC: 24903 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 15213 AN: 26134

East Asian (EAS) AF: 0.525 AC: 20840 AN: 39688

South Asian (SAS) AF: 0.410 AC: 35354 AN: 86250

European-Finnish (FIN) AF: 0.589 AC: 31460 AN: 53380

Middle Eastern (MID) AF: 0.507 AC: 2925 AN: 5768

European-Non Finnish (NFE) AF: 0.585 AC: 650736 AN: 1111772

Other (OTH) AF: 0.541 AC: 32664 AN: 60384

GnomAD4 genome AF: 0.465 AC: 70680 AN: 151928 Hom.: 18607 Cov.: 31 AF XY: 0.469 AC XY: 34777 AN XY: 74228

African (AFR) AF: 0.199 AC: 8240 AN: 41450

American (AMR) AF: 0.544 AC: 8283 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2025 AN: 3466

East Asian (EAS) AF: 0.574 AC: 2954 AN: 5148

South Asian (SAS) AF: 0.409 AC: 1967 AN: 4808

European-Finnish (FIN) AF: 0.595 AC: 6273 AN: 10544

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.576 AC: 39146 AN: 67968

Other (OTH) AF: 0.505 AC: 1066 AN: 2112

Alfa AF: 0.539 Hom.: 4657

EpiCase AF: 0.563

EpiControl AF: 0.570

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial cold autoinflammatory syndrome 2 (3)
-	-	3	not specified (3)
-	-	1	Familial cold autoinflammatory syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.1
DANN	Benign	0.56
PhyloP100		0.0060
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12460528; hg19: chr19-54307322; COSMIC: COSV60743403;