rs269913

chr19-54970301-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017852.5(NLRP2):c.280+6T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 1,613,434 control chromosomes in the GnomAD database, including 194,442 homozygotes. 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: 𝑓 0.53 (22190 hom., cov: 31)
  • Exomes 𝑓: 0.48 (172252 hom.)
• Consequence: NLRP2 NM_017852.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0002838
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP2	NM_017852.5	c.280+6T>C		splice_donor_region_variant, intron_variant		ENST00000448584.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP2	ENST00000448584.7	c.280+6T>C		splice_donor_region_variant, intron_variant		1	NM_017852.5	P2

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80074 AN: 151680 Hom.: 22178 Cov.: 31

Gnomad AFR AF: 0.693

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.500

GnomAD3 exomes AF: 0.449 AC: 112397 AN: 250212 Hom.: 26684 AF XY: 0.438 AC XY: 59306 AN XY: 135364

Gnomad AFR exome AF: 0.704

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.380

Gnomad EAS exome AF: 0.419

Gnomad SAS exome AF: 0.276

Gnomad FIN exome AF: 0.452

Gnomad NFE exome AF: 0.490

Gnomad OTH exome AF: 0.445

GnomAD4 exome AF: 0.480 AC: 701876 AN: 1461636 Hom.: 172252 Cov.: 49 AF XY: 0.474 AC XY: 344562 AN XY: 727136

Gnomad4 AFR exome AF: 0.700

Gnomad4 AMR exome AF: 0.389

Gnomad4 ASJ exome AF: 0.381

Gnomad4 EAS exome AF: 0.470

Gnomad4 SAS exome AF: 0.280

Gnomad4 FIN exome AF: 0.451

Gnomad4 NFE exome AF: 0.498

Gnomad4 OTH exome AF: 0.468

GnomAD4 genome AF: 0.528 AC: 80121 AN: 151798 Hom.: 22190 Cov.: 31 AF XY: 0.519 AC XY: 38504 AN XY: 74164

Gnomad4 AFR AF: 0.693

Gnomad4 AMR AF: 0.430

Gnomad4 ASJ AF: 0.382

Gnomad4 EAS AF: 0.431

Gnomad4 SAS AF: 0.269

Gnomad4 FIN AF: 0.431

Gnomad4 NFE AF: 0.500

Gnomad4 OTH AF: 0.494

Alfa AF: 0.496 Hom.: 11428

Bravo AF: 0.536

Asia WGS AF: 0.321 AC: 1117 AN: 3478

EpiCase AF: 0.488

EpiControl AF: 0.485

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.26
Dann	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.068
SpliceAI score (max)		0.020		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: rs269913; hg19: chr19-55481669;