19-53801229-C-G

Variant names:

• chr19-53801229-C-G
• rs61741347
• NM_144687.4:c.2754G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_144687.4(NLRP12):​c.2754G>C​(p.Leu918Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,613,836 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L918L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (11 hom., cov: 30)
  • Exomes 𝑓: 0.00066 (14 hom.)
• Consequence: NLRP12 NM_144687.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001244
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.966
• Publications: 1 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=-0.92).
• BP6: Variant 19-53801229-C-G is Benign according to our data. Variant chr19-53801229-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 330011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.966 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00642 (976/151996) while in subpopulation AFR AF = 0.0215 (893/41474). AF 95% confidence interval is 0.0204. There are 11 homozygotes in GnomAd4. There are 458 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 976 AD gene.

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.2754G>C	p.Leu918Leu	splice_region synonymous	Exon 7 of 10	NP_653288.1	P59046-1
	NLRP12	NM_001277126.2		c.2757G>C	p.Leu919Leu	splice_region synonymous	Exon 7 of 10	NP_001264055.1	P59046-7
	NLRP12	NM_001277129.1		c.2754G>C	p.Leu918Leu	splice_region synonymous	Exon 7 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.2754G>C	p.Leu918Leu	splice_region synonymous	Exon 7 of 10	ENSP00000319377.6	P59046-1
	NLRP12	ENST00000391773.8	TSL:1	c.2757G>C	p.Leu919Leu	splice_region synonymous	Exon 7 of 10	ENSP00000375653.1	P59046-7
	NLRP12	ENST00000345770.9	TSL:1	c.2757G>C	p.Leu919Leu	splice_region synonymous	Exon 7 of 9	ENSP00000341428.5	A0A0C4DH17

Frequencies

GnomAD3 genomes AF: 0.00638 AC: 969 AN: 151880 Hom.: 11 Cov.: 30

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00389

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00767

GnomAD2 exomes AF: 0.00163 AC: 407 AN: 250372 AF XY: 0.00121

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000662 AC: 968 AN: 1461840 Hom.: 14 Cov.: 35 AF XY: 0.000586 AC XY: 426 AN XY: 727216

African (AFR) AF: 0.0214 AC: 717 AN: 33480

American (AMR) AF: 0.00177 AC: 79 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111976

Other (OTH) AF: 0.00199 AC: 120 AN: 60394

GnomAD4 genome AF: 0.00642 AC: 976 AN: 151996 Hom.: 11 Cov.: 30 AF XY: 0.00617 AC XY: 458 AN XY: 74272

African (AFR) AF: 0.0215 AC: 893 AN: 41474

American (AMR) AF: 0.00388 AC: 59 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67988

Other (OTH) AF: 0.00759 AC: 16 AN: 2108

Alfa AF: 0.000659 Hom.: 0

Bravo AF: 0.00743

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial cold autoinflammatory syndrome 2 (3)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	NLRP12-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.9
DANN	Benign	0.55
PhyloP100		-0.97
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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: rs61741347; hg19: chr19-54304483;