19-54970030-G-A

Variant names:

• chr19-54970030-G-A
• rs269912
• NM_017852.5:c.15G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_017852.5(NLRP2):​c.15G>A​(p.Ala5Ala) 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.14 (2008 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28986 hom.)
• Consequence: NLRP2 NM_017852.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.28
• Publications: 17 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-54970030-G-A is Benign according to our data. Variant chr19-54970030-G-A is described in ClinVar as Benign. ClinVar VariationId is 3055369.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 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.15G>A	p.Ala5Ala	synonymous	Exon 2 of 13	NP_060322.1	Q9NX02-1
	NLRP2	NM_001174081.3		c.15G>A	p.Ala5Ala	synonymous	Exon 2 of 13	NP_001167552.1	Q9NX02-1
	NLRP2	NM_001348003.2		c.15G>A	p.Ala5Ala	synonymous	Exon 2 of 13	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.15G>A	p.Ala5Ala	synonymous	Exon 2 of 13	ENSP00000409370.2	Q9NX02-1
	NLRP2	ENST00000543010.5	TSL:1	c.15G>A	p.Ala5Ala	synonymous	Exon 2 of 13	ENSP00000445135.1	Q9NX02-1
	NLRP2	ENST00000263437.10	TSL:2	c.15G>A	p.Ala5Ala	synonymous	Exon 2 of 13	ENSP00000263437.6	J3KN39

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21686 AN: 151904 Hom.: 2011 Cov.: 32

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

GnomAD2 exomes AF: 0.147 AC: 36836 AN: 251370 AF XY: 0.148

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 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

African (AFR) AF: 0.0349 AC: 1167 AN: 33466

American (AMR) AF: 0.0906 AC: 4051 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3475 AN: 26134

East Asian (EAS) AF: 0.0555 AC: 2202 AN: 39696

South Asian (SAS) AF: 0.0713 AC: 6148 AN: 86240

European-Finnish (FIN) AF: 0.211 AC: 11288 AN: 53416

Middle Eastern (MID) AF: 0.0928 AC: 509 AN: 5486

European-Non Finnish (NFE) AF: 0.215 AC: 239132 AN: 1111902

Other (OTH) AF: 0.166 AC: 10048 AN: 60362

GnomAD4 genome AF: 0.143 AC: 21673 AN: 152022 Hom.: 2008 Cov.: 32 AF XY: 0.142 AC XY: 10562 AN XY: 74286

African (AFR) AF: 0.0421 AC: 1747 AN: 41508

American (AMR) AF: 0.123 AC: 1873 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 451 AN: 3466

East Asian (EAS) AF: 0.0438 AC: 226 AN: 5154

South Asian (SAS) AF: 0.0581 AC: 280 AN: 4820

European-Finnish (FIN) AF: 0.212 AC: 2232 AN: 10552

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14412 AN: 67984

Other (OTH) AF: 0.149 AC: 315 AN: 2112

Alfa AF: 0.184 Hom.: 8991

Bravo AF: 0.130

Asia WGS AF: 0.0460 AC: 162 AN: 3478

EpiCase AF: 0.200

EpiControl AF: 0.198

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NLRP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.98
DANN	Benign	0.44
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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