chr19-53810436-C-A

Variant names:

• chr19-53810436-C-A
• rs774895361
• NM_144687.4:c.1223G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_144687.4(NLRP12):​c.1223G>T​(p.Trp408Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP12 NM_144687.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.28
• Publications: 4 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

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.1223G>T	p.Trp408Leu	missense	Exon 3 of 10	NP_653288.1
	NLRP12	NM_001277126.2		c.1223G>T	p.Trp408Leu	missense	Exon 3 of 10	NP_001264055.1
	NLRP12	NM_001277129.1		c.1223G>T	p.Trp408Leu	missense	Exon 3 of 9	NP_001264058.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	ENST00000324134.11	TSL:1 MANE Select	c.1223G>T	p.Trp408Leu	missense	Exon 3 of 10	ENSP00000319377.6
	NLRP12	ENST00000391773.8	TSL:1	c.1223G>T	p.Trp408Leu	missense	Exon 3 of 10	ENSP00000375653.1
	NLRP12	ENST00000345770.9	TSL:1	c.1223G>T	p.Trp408Leu	missense	Exon 3 of 9	ENSP00000341428.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.028	D
Sift4G	Benign	0.077	T
Polyphen		1.0	D
Vest4		0.72
MutPred		0.75		Loss of helix (P = 0.2271)
MVP		0.97
MPC		0.45
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.60
gMVP		0.55
Mutation Taster		=16/84	disease causing

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: rs774895361; hg19: chr19-54313690;