19-54970026-C-T

Position:

chr19-54970026-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017852.5(NLRP2):c.11C>T(p.Ser4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00941 in 1,613,550 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 14 hom., cov: 32)

Exomes 𝑓: 0.0096 ( 95 hom. )

Consequence

NLRP2
NM_017852.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.186

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050066113).

BP6

Variant 19-54970026-C-T is Benign according to our data. Variant chr19-54970026-C-T is described in ClinVar as [Benign]. Clinvar id is 778857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00724 (1102/152146) while in subpopulation SAS AF= 0.0218 (105/4820). AF 95% confidence interval is 0.0184. There are 14 homozygotes in gnomad4. There are 514 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.11C>T	p.Ser4Leu	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.11C>T	p.Ser4Leu	missense_variant	2/13	1	NM_017852.5	ENSP00000409370.2		Q9NX02-1

Frequencies

GnomAD3 genomes

AF:

0.00726

AC:

1104

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.00493

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.0222

Gnomad FIN

AF:

0.00396

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00998

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00907

AC:

2279

AN:

251388

Hom.:

AF XY:

0.00985

AC XY:

1338

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.00532

Gnomad ASJ exome

AF:

0.0151

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0219

Gnomad FIN exome

AF:

0.00448

Gnomad NFE exome

AF:

0.00940

Gnomad OTH exome

AF:

0.00929

GnomAD4 exome

AF:

0.00963

AC:

14077

AN:

1461404

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

7312

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.00284

Gnomad4 AMR exome

AF:

0.00546

Gnomad4 ASJ exome

AF:

0.0170

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0208

Gnomad4 FIN exome

AF:

0.00545

Gnomad4 NFE exome

AF:

0.00949

Gnomad4 OTH exome

AF:

0.0101

GnomAD4 genome

AF:

0.00724

AC:

1102

AN:

152146

Hom.:

Cov.:

AF XY:

0.00691

AC XY:

514

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00277

Gnomad4 AMR

AF:

0.00492

Gnomad4 ASJ

AF:

0.0164

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.0218

Gnomad4 FIN

AF:

0.00396

Gnomad4 NFE

AF:

0.00999

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00839

Hom.:

Bravo

AF:

0.00617

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00919

AC:

ExAC

AF:

0.00923

AC:

1120

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0100

EpiControl

AF:

0.0104

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

NLRP2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 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

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

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

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.012

MetaRNN

Benign

0.0050

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

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.5

.;.;.;M;M;M;M;M;M;.

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-4.1

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

REVEL

Benign

0.12

Sift

Uncertain

0.0080

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

Sift4G

Uncertain

0.015

D;D;D;D;D;D;D;D;D;D

Polyphen

0.99, 1.0

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

Vest4

0.23, 0.24, 0.22, 0.23, 0.23

MVP

0.67

MPC

0.056

ClinPred

0.032

GERP RS

0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.098

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