19-54970302-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_017852.5(NLRP2):c.280+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,613,996 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (16 hom.)
• Consequence: NLRP2 NM_017852.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001984
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.489

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 19-54970302-G-A is Benign according to our data. Variant chr19-54970302-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2650498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP2	NM_017852.5	c.280+7G>A		splice_region_variant, intron_variant		ENST00000448584.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP2	ENST00000448584.7	c.280+7G>A		splice_region_variant, intron_variant		1	NM_017852.5	P2

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 343 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00373

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00196 AC: 491 AN: 250294 Hom.: 2 AF XY: 0.00203 AC XY: 275 AN XY: 135428

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00281

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00325 AC: 4747 AN: 1461772 Hom.: 16 Cov.: 34 AF XY: 0.00318 AC XY: 2312 AN XY: 727198

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00463

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00167

Gnomad4 FIN exome AF: 0.000505

Gnomad4 NFE exome AF: 0.00369

Gnomad4 OTH exome AF: 0.00391

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152224 Hom.: 0 Cov.: 31 AF XY: 0.00207 AC XY: 154 AN XY: 74414

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00317 Hom.: 1

Bravo AF: 0.00244

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00326

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NLRP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

NLRP2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.35
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
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: rs201587755; hg19: chr19-55481670;