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GeneBe

19-54970030-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_017852.5(NLRP2):c.15G>A(p.Ala5=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,613,442 control chromosomes in the GnomAD database, including 30,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.14 ( 2008 hom., cov: 32)
Exomes 𝑓: 0.19 ( 28986 hom. )

Consequence

NLRP2
NM_017852.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.28
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.91).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-54970030-G-A is Benign according to our data. Variant chr19-54970030-G-A is described in ClinVar as [Benign]. Clinvar id is 3055369.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-1.28 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NLRP2NM_017852.5 linkuse as main transcriptc.15G>A p.Ala5= synonymous_variant 2/13 ENST00000448584.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NLRP2ENST00000448584.7 linkuse as main transcriptc.15G>A p.Ala5= synonymous_variant 2/131 NM_017852.5 P2Q9NX02-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.143
AC:
21686
AN:
151904
Hom.:
2011
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0421
Gnomad AMI
AF:
0.107
Gnomad AMR
AF:
0.123
Gnomad ASJ
AF:
0.130
Gnomad EAS
AF:
0.0443
Gnomad SAS
AF:
0.0593
Gnomad FIN
AF:
0.212
Gnomad MID
AF:
0.133
Gnomad NFE
AF:
0.212
Gnomad OTH
AF:
0.151
GnomAD3 exomes
AF:
0.147
AC:
36836
AN:
251370
Hom.:
3417
AF XY:
0.148
AC XY:
20081
AN XY:
135874
show subpopulations
Gnomad AFR exome
AF:
0.0384
Gnomad AMR exome
AF:
0.0884
Gnomad ASJ exome
AF:
0.130
Gnomad EAS exome
AF:
0.0444
Gnomad SAS exome
AF:
0.0695
Gnomad FIN exome
AF:
0.213
Gnomad NFE exome
AF:
0.205
Gnomad OTH exome
AF:
0.157
GnomAD4 exome
AF:
0.190
AC:
278020
AN:
1461420
Hom.:
28986
Cov.:
50
AF XY:
0.187
AC XY:
136174
AN XY:
727020
show subpopulations
Gnomad4 AFR exome
AF:
0.0349
Gnomad4 AMR exome
AF:
0.0906
Gnomad4 ASJ exome
AF:
0.133
Gnomad4 EAS exome
AF:
0.0555
Gnomad4 SAS exome
AF:
0.0713
Gnomad4 FIN exome
AF:
0.211
Gnomad4 NFE exome
AF:
0.215
Gnomad4 OTH exome
AF:
0.166
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.143
AC:
21673
AN:
152022
Hom.:
2008
Cov.:
32
AF XY:
0.142
AC XY:
10562
AN XY:
74286
show subpopulations
Gnomad4 AFR
AF:
0.0421
Gnomad4 AMR
AF:
0.123
Gnomad4 ASJ
AF:
0.130
Gnomad4 EAS
AF:
0.0438
Gnomad4 SAS
AF:
0.0581
Gnomad4 FIN
AF:
0.212
Gnomad4 NFE
AF:
0.212
Gnomad4 OTH
AF:
0.149
Alfa
AF:
0.186
Hom.:
4251
Bravo
AF:
0.130
Asia WGS
AF:
0.0460
AC:
162
AN:
3478
EpiCase
AF:
0.200
EpiControl
AF:
0.198

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

NLRP2-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 25, 2019This 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
BayesDel_noAF
Benign
-0.91
Cadd
Benign
0.98
Dann
Benign
0.44
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs269912; hg19: chr19-55481398; COSMIC: COSV54755146; COSMIC: COSV54755146; API