19-54970388-C-G

Variant names:

• chr19-54970388-C-G
• rs199475707
• NM_017852.5:c.280+93C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017852.5(NLRP2):​c.280+93C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000228 in 1,318,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 31)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: NLRP2 NM_017852.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0360
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP2	NM_017852.5	MANE Select	c.280+93C>G		intron	N/A	NP_060322.1	Q9NX02-1
	NLRP2	NM_001174081.3		c.280+93C>G		intron	N/A	NP_001167552.1	Q9NX02-1
	NLRP2	NM_001348003.2		c.280+93C>G		intron	N/A	NP_001334932.1	J3KN39

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP2	ENST00000448584.7	TSL:1 MANE Select	c.280+93C>G		intron	N/A	ENSP00000409370.2	Q9NX02-1
	NLRP2	ENST00000543010.5	TSL:1	c.280+93C>G		intron	N/A	ENSP00000445135.1	Q9NX02-1
	NLRP2	ENST00000263437.10	TSL:2	c.280+93C>G		intron	N/A	ENSP00000263437.6	J3KN39

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000228 AC: 3 AN: 1318638 Hom.: 0 AF XY: 0.00000302 AC XY: 2 AN XY: 661686

African (AFR) AF: 0.00 AC: 0 AN: 30748

American (AMR) AF: 0.0000714 AC: 3 AN: 42014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25018

East Asian (EAS) AF: 0.00 AC: 0 AN: 38946

South Asian (SAS) AF: 0.00 AC: 0 AN: 82308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5434

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 989678

Other (OTH) AF: 0.00 AC: 0 AN: 55658

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.33
DANN	Benign	0.54
PhyloP100		-0.036

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: rs199475707; hg19: chr19-55481756;