19-55000769-C-G

Variant names:

• chr19-55000769-C-G
• rs12768
• NM_017852.5:c.3060C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017852.5(NLRP2):​c.3060C>G​(p.Ile1020Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NLRP2 NM_017852.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56
• Publications: 29 publications found

Genes affected

NLRP2 (HGNC:22948): (NLR family pyrin domain containing 2) This gene is a member of the nucleotide-binding and leucine-rich repeat receptor (NLR) family, and is predicted to contain an N-terminal pyrin effector domain (PYD), a centrally-located nucleotide-binding and oligomerization domain (NACHT) and C-terminal leucine-rich repeats (LRR). Members of this gene family are thought to be important regulators of immune responses. This gene product interacts with components of the IkB kinase (IKK) complex, and can regulate both caspase-1 and NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity. The pyrin domain is necessary and sufficient for suppression of NF-kB activity. An allelic variant (rs147585490) has been found that is incapable of blocking the transcriptional activity of NF-kB. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

NLRP2 Gene-Disease associations (from GenCC):

• oocyte/zygote/embryo maturation arrest 18

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.084673375).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017852.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP2	NM_017852.5	MANE Select	c.3060C>G	p.Ile1020Met	missense	Exon 13 of 13	NP_060322.1
	NLRP2	NM_001174081.3		c.3060C>G	p.Ile1020Met	missense	Exon 13 of 13	NP_001167552.1
	NLRP2	NM_001348003.2		c.3051C>G	p.Ile1017Met	missense	Exon 13 of 13	NP_001334932.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP2	ENST00000448584.7	TSL:1 MANE Select	c.3060C>G	p.Ile1020Met	missense	Exon 13 of 13	ENSP00000409370.2
	NLRP2	ENST00000543010.5	TSL:1	c.3060C>G	p.Ile1020Met	missense	Exon 13 of 13	ENSP00000445135.1
	NLRP2	ENST00000263437.10	TSL:2	c.3051C>G	p.Ile1017Met	missense	Exon 13 of 13	ENSP00000263437.6

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251324 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461226 Hom.: 0 Cov.: 40 AF XY: 0.00000275 AC XY: 2 AN XY: 726974

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111466

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 36022

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.046
DANN	Benign	0.48
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0025	N
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-1.6
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.047
Sift	Benign	0.20	T
Sift4G	Benign	0.092	T
Polyphen		0.60	P
Vest4		0.14
MutPred		0.52		Gain of disorder (P = 0.0267)
MVP		0.45
MPC		0.056
ClinPred		0.067	T
GERP RS		-6.3
Varity_R		0.041
gMVP		0.11
Mutation Taster		=94/6	polymorphism

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: rs12768; hg19: chr19-55512137;