Genetic Variant NM_017852.5:c.281-82G>A (chr19-54974418-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_017852.5(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
NM_017852.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.05

Publications

4 publications found

Variant links:

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 links:

RPL36AP50 (HGNC:36372): (ribosomal protein L36a pseudogene 50)

RPL36AP50 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
NLRP2	NM_017852.5 link	c.281-82G>A		intron_variant	Intron 2 of 12	ENST00000448584.7	NP_060322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP2	ENST00000448584.7 link	c.281-82G>A		intron_variant	Intron 2 of 12	1	NM_017852.5	ENSP00000409370.2		Q9NX02-1

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34450

AN:

151890

Hom.:

4065

Cov.:

show subpopulations

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.:

AF XY:

0.223

AC XY:

97125

AN XY:

435622

show subpopulations

African (AFR)

AF:

0.240

AC:

5067

AN:

21128

American (AMR)

AF:

0.247

AC:

10649

AN:

43102

Ashkenazi Jewish (ASJ)

AF:

0.208

AC:

4588

AN:

22096

East Asian (EAS)

AF:

0.399

AC:

14695

AN:

36792

South Asian (SAS)

AF:

0.201

AC:

14682

AN:

73006

European-Finnish (FIN)

AF:

0.184

AC:

9646

AN:

52320

Middle Eastern (MID)

AF:

0.246

AC:

975

AN:

3962

European-Non Finnish (NFE)

AF:

0.217

AC:

115568

AN:

531750

Other (OTH)

AF:

0.220

AC:

8637

AN:

39254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

6313

12625

18938

25250

31563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2392

4784

7176

9568

11960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.227

AC:

34457

AN:

152006

Hom.:

4060

Cov.:

AF XY:

0.225

AC XY:

16711

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.236

AC:

9810

AN:

41492

American (AMR)

AF:

0.220

AC:

3359

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.217

AC:

754

AN:

3470

East Asian (EAS)

AF:

0.380

AC:

1959

AN:

5162

South Asian (SAS)

AF:

0.205

AC:

985

AN:

4816

European-Finnish (FIN)

AF:

0.173

AC:

1832

AN:

10582

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.222

AC:

15082

AN:

67934

Other (OTH)

AF:

0.222

AC:

467

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1364

2727

4091

5454

6818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

360

720

1080

1440

1800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.234

Hom.:

1277

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

(source)

DANN

Benign

0.44

PhyloP100

1.0

PromoterAI

-0.0078

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over