rs703468

Positions:

• chr19-54974418-G-A
• chr19-54974418-G-C

Variant summary

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

The ENST00000448584.7(NLRP2):​c.281-82G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 975,416 control chromosomes in the GnomAD database, including 25,965 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 0.23 (4060 hom., cov: 32)
  • Exomes 𝑓: 0.22 (21905 hom.)
• Consequence: NLRP2 ENST00000448584.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP2	NM_017852.5	c.281-82G>A		intron_variant		ENST00000448584.7	NP_060322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP2	ENST00000448584.7	c.281-82G>A		intron_variant		1	NM_017852.5	ENSP00000409370	P2
RPL36AP50	ENST00000466725.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34450 AN: 151890 Hom.: 4065 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.224

GnomAD4 exome AF: 0.224 AC: 184507 AN: 823410 Hom.: 21905 Cov.: 12 AF XY: 0.223 AC XY: 97125 AN XY: 435622

Gnomad4 AFR exome AF: 0.240

Gnomad4 AMR exome AF: 0.247

Gnomad4 ASJ exome AF: 0.208

Gnomad4 EAS exome AF: 0.399

Gnomad4 SAS exome AF: 0.201

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.217

Gnomad4 OTH exome AF: 0.220

GnomAD4 genome AF: 0.227 AC: 34457 AN: 152006 Hom.: 4060 Cov.: 32 AF XY: 0.225 AC XY: 16711 AN XY: 74330

Gnomad4 AFR AF: 0.236

Gnomad4 AMR AF: 0.220

Gnomad4 ASJ AF: 0.217

Gnomad4 EAS AF: 0.380

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.173

Gnomad4 NFE AF: 0.222

Gnomad4 OTH AF: 0.222

Alfa AF: 0.229 Hom.: 510

Bravo AF: 0.232

Asia WGS AF: 0.238 AC: 829 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.0
DANN	Benign	0.44

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: rs703468; hg19: chr19-55485786; COSMIC: COSV54759354; COSMIC: COSV54759354;