19-54974531-G-C

Variant names:

• chr19-54974531-G-C
• rs2217659
• NM_017852.5:c.312G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017852.5(NLRP2):​c.312G>C​(p.Lys104Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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: 32)
• Consequence: NLRP2 NM_017852.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.100

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]

RPL36AP50 (HGNC:36372): (ribosomal protein L36a pseudogene 50)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08874011).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP2	NM_017852.5	c.312G>C	p.Lys104Asn	missense_variant	Exon 3 of 13	ENST00000448584.7	NP_060322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP2	ENST00000448584.7	c.312G>C	p.Lys104Asn	missense_variant	Exon 3 of 13	1	NM_017852.5	ENSP00000409370.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.3
DANN	Benign	0.86
DEOGEN2	Benign	0.013	.;.;T;T;.;.;T;.;T;.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.013	N
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.089	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.90	.;.;.;L;L;L;L;L;.;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.91	.;.;N;N;N;N;N;N;.;N;N;D
REVEL	Benign	0.11
Sift	Uncertain	0.0040	.;.;D;D;T;T;D;T;.;T;T;D
Sift4G	Uncertain	0.016	D;D;D;D;T;T;D;T;T;T;D;D
Polyphen		0.79, 0.65	.;.;.;P;P;P;P;P;.;.;.;.
Vest4		0.23, 0.24, 0.25, 0.25, 0.29, 0.22
MutPred		0.31		Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);.;.;Loss of loop (P = 0.0073);.;
MVP		0.39
MPC		0.22
ClinPred		0.20	T
GERP RS		-2.6
Varity_R		0.098
gMVP		0.063

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

Publications

LitVar

Other links and lift over

dbSNP: rs2217659; hg19: chr19-55485899;