19-54970087-C-G

Position:

chr19-54970087-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017852.5(NLRP2):c.72C>G(p.Ser24Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,614,040 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0062 ( 14 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 10 hom. )

Consequence

NLRP2
NM_017852.5 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.720

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044365227).

BP6

Variant 19-54970087-C-G is Benign according to our data. Variant chr19-54970087-C-G is described in ClinVar as [Benign]. Clinvar id is 3039591.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00622 (946/152154) while in subpopulation AFR AF= 0.0217 (899/41520). AF 95% confidence interval is 0.0205. There are 14 homozygotes in gnomad4. There are 453 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP2	NM_017852.5 link	c.72C>G	p.Ser24Arg	missense_variant	2/13	ENST00000448584.7	NP_060322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP2	ENST00000448584.7 link	c.72C>G	p.Ser24Arg	missense_variant	2/13	1	NM_017852.5	ENSP00000409370.2		Q9NX02-1

Frequencies

GnomAD3 genomes

AF:

0.00622

AC:

946

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00173

AC:

435

AN:

251480

Hom.:

AF XY:

0.00129

AC XY:

176

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0231

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000595

AC:

870

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000513

AC XY:

373

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0212

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00121

GnomAD4 genome

AF:

0.00622

AC:

946

AN:

152154

Hom.:

Cov.:

AF XY:

0.00609

AC XY:

453

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0217

Gnomad4 AMR

AF:

0.00223

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000935

Hom.:

Bravo

AF:

0.00702

ESP6500AA

AF:

0.0209

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00215

AC:

261

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NLRP2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 14, 2019

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

.;.;T;T;.;.;T;.;.;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.023

MetaRNN

Benign

0.0044

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;.;.;L;L;L;L;L;L;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.4

.;.;N;N;N;N;N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.030

.;.;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D;D;D;D;D;T;D

Polyphen

0.94, 0.93

.;.;.;P;P;P;P;P;.;.

Vest4

0.36, 0.40, 0.37, 0.37, 0.38, 0.38

MutPred

0.48

Loss of ubiquitination at K25 (P = 0.0603);Loss of ubiquitination at K25 (P = 0.0603);Loss of ubiquitination at K25 (P = 0.0603);Loss of ubiquitination at K25 (P = 0.0603);Loss of ubiquitination at K25 (P = 0.0603);Loss of ubiquitination at K25 (P = 0.0603);Loss of ubiquitination at K25 (P = 0.0603);Loss of ubiquitination at K25 (P = 0.0603);Loss of ubiquitination at K25 (P = 0.0603);Loss of ubiquitination at K25 (P = 0.0603);

MVP

0.66

MPC

0.29

ClinPred

0.0097

GERP RS

1.9

Varity_R

0.14

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over