19-54970301-T-C

Variant names:

• chr19-54970301-T-C
• rs269913
• NM_017852.5:c.280+6T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017852.5(NLRP2):​c.280+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 1,613,434 control chromosomes in the GnomAD database, including 194,442 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.0002838
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85
• Publications: 32 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: Benign. The variant received -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.

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+6T>C		splice_region intron	N/A	NP_060322.1	Q9NX02-1
	NLRP2	NM_001174081.3		c.280+6T>C		splice_region intron	N/A	NP_001167552.1	Q9NX02-1
	NLRP2	NM_001348003.2		c.280+6T>C		splice_region 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+6T>C		splice_region intron	N/A	ENSP00000409370.2	Q9NX02-1
	NLRP2	ENST00000543010.5	TSL:1	c.280+6T>C		splice_region intron	N/A	ENSP00000445135.1	Q9NX02-1
	NLRP2	ENST00000263437.10	TSL:2	c.280+6T>C		splice_region intron	N/A	ENSP00000263437.6	J3KN39

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

GnomAD2 exomes AF: 0.449 AC: 112397 AN: 250212 AF XY: 0.438

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 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

African (AFR) AF: 0.700 AC: 23425 AN: 33480

American (AMR) AF: 0.389 AC: 17409 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 9951 AN: 26136

East Asian (EAS) AF: 0.470 AC: 18669 AN: 39698

South Asian (SAS) AF: 0.280 AC: 24117 AN: 86248

European-Finnish (FIN) AF: 0.451 AC: 24079 AN: 53412

Middle Eastern (MID) AF: 0.388 AC: 2239 AN: 5768

European-Non Finnish (NFE) AF: 0.498 AC: 553746 AN: 1111794

Other (OTH) AF: 0.468 AC: 28241 AN: 60388

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

African (AFR) AF: 0.693 AC: 28729 AN: 41436

American (AMR) AF: 0.430 AC: 6543 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1323 AN: 3466

East Asian (EAS) AF: 0.431 AC: 2213 AN: 5140

South Asian (SAS) AF: 0.269 AC: 1295 AN: 4810

European-Finnish (FIN) AF: 0.431 AC: 4537 AN: 10528

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.500 AC: 33928 AN: 67916

Other (OTH) AF: 0.494 AC: 1039 AN: 2102

Alfa AF: 0.501 Hom.: 19044

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.26
DANN	Benign	0.35
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs269913; hg19: chr19-55481669; COSMIC: COSV107216582; COSMIC: COSV107216582;