19-53804068-G-T

Variant names:

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

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>A​(p.Leu823Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0827 in 1,613,674 control chromosomes in the GnomAD database, including 6,215 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 0.061 (399 hom., cov: 31)
  • Exomes 𝑓: 0.085 (5816 hom.)
• Consequence: NLRP12 NM_144687.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• 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=-0.81).
• BP6: Variant 19-53804068-G-T is Benign according to our data. Variant chr19-53804068-G-T is described in ClinVar as Benign. ClinVar VariationId is 262530.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 (SAS) allele frequency at 95% confidence interval = 0.117 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>A	p.Leu823Leu	synonymous	Exon 6 of 10	NP_653288.1	P59046-1
	NLRP12	NM_001277126.2		c.2472C>A	p.Leu824Leu	synonymous	Exon 6 of 10	NP_001264055.1	P59046-7
	NLRP12	NM_001277129.1		c.2469C>A	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>A	p.Leu823Leu	synonymous	Exon 6 of 10	ENSP00000319377.6	P59046-1
	NLRP12	ENST00000391773.8	TSL:1	c.2472C>A	p.Leu824Leu	synonymous	Exon 6 of 10	ENSP00000375653.1	P59046-7
	NLRP12	ENST00000345770.9	TSL:1	c.2472C>A	p.Leu824Leu	synonymous	Exon 6 of 9	ENSP00000341428.5	A0A0C4DH17

Frequencies

GnomAD3 genomes AF: 0.0611 AC: 9283 AN: 151850 Hom.: 397 Cov.: 31

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.0492

Gnomad ASJ AF: 0.0666

Gnomad EAS AF: 0.000969

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0932

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0879

Gnomad OTH AF: 0.0531

GnomAD2 exomes AF: 0.0736 AC: 18480 AN: 251008 AF XY: 0.0780

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.0612

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0943

Gnomad NFE exome AF: 0.0905

Gnomad OTH exome AF: 0.0773

GnomAD4 exome AF: 0.0849 AC: 124095 AN: 1461704 Hom.: 5816 Cov.: 48 AF XY: 0.0863 AC XY: 62765 AN XY: 727154

African (AFR) AF: 0.0127 AC: 424 AN: 33478

American (AMR) AF: 0.0337 AC: 1508 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0621 AC: 1624 AN: 26134

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39692

South Asian (SAS) AF: 0.125 AC: 10786 AN: 86252

European-Finnish (FIN) AF: 0.0988 AC: 5275 AN: 53384

Middle Eastern (MID) AF: 0.0896 AC: 517 AN: 5768

European-Non Finnish (NFE) AF: 0.0892 AC: 99142 AN: 1111908

Other (OTH) AF: 0.0796 AC: 4809 AN: 60390

GnomAD4 genome AF: 0.0611 AC: 9290 AN: 151970 Hom.: 399 Cov.: 31 AF XY: 0.0615 AC XY: 4563 AN XY: 74236

African (AFR) AF: 0.0142 AC: 589 AN: 41468

American (AMR) AF: 0.0491 AC: 748 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.0666 AC: 231 AN: 3466

East Asian (EAS) AF: 0.000971 AC: 5 AN: 5148

South Asian (SAS) AF: 0.126 AC: 605 AN: 4812

European-Finnish (FIN) AF: 0.0932 AC: 983 AN: 10542

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0879 AC: 5977 AN: 67982

Other (OTH) AF: 0.0521 AC: 110 AN: 2112

Alfa AF: 0.0388 Hom.: 4657

EpiCase AF: 0.0859

EpiControl AF: 0.0837

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.43
DANN	Benign	0.52
PhyloP100		0.0060
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs12460528; hg19: chr19-54307322;