Variant 3-50347830-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006545.5(NPRL2):c.1004G>A(p.Arg335Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

NPRL2
NM_006545.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.33

Variant links:

Genes affected

NPRL2 (HGNC:24969): (NPR2 like, GATOR1 complex subunit) Enables protein kinase activity. Contributes to GTPase activator activity. Involved in cellular response to amino acid starvation; negative regulation of TOR signaling; and negative regulation of kinase activity. Located in lysosomal membrane. Part of GATOR1 complex. Implicated in focal epilepsy. [provided by Alliance of Genome Resources, Apr 2022]

NPRL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08223587).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NPRL2	NM_006545.5 linkuse as main transcript	c.1004G>A	p.Arg335Gln	missense_variant	10/11	ENST00000232501.8
NPRL2	XM_047447310.1 linkuse as main transcript	c.1082G>A	p.Arg361Gln	missense_variant	10/11
NPRL2	XM_011533288.4 linkuse as main transcript	c.995G>A	p.Arg332Gln	missense_variant	9/10
NPRL2	XM_017005556.3 linkuse as main transcript	c.644G>A	p.Arg215Gln	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPRL2	ENST00000232501.8 linkuse as main transcript	c.1004G>A	p.Arg335Gln	missense_variant	10/11	1	NM_006545.5	P1	Q8WTW4-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251364

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000486

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Epilepsy, familial focal, with variable foci 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

May 31, 2020

The NPRL2:c.1004G>A variant results in a single nucleotide change from a guanine to an adenine at position 1004 in exon 10 of the NPRL2 gene. This results in the substitution of a glutamine for the wild type arginine residue at position 335. The variant is located in the nitrogen permease regulator 2 domain. It is a weakly conserved amino acid; Metadome considers the protein neutral to variation at this position. In silico pathogenicity predictions are conflicting. There are 3 heterozygotes out of 251364 alleles in gnomAD (PM2). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.027

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.76

M_CAP

Benign

0.0075

MetaRNN

Benign

0.082

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.95

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.50

REVEL

Benign

0.062

Sift

Benign

0.52

Sift4G

Benign

0.58

Polyphen

0.012

Vest4

0.14

MutPred

0.57

Loss of MoRF binding (P = 0.0397);

MVP

0.18

MPC

0.62

ClinPred

0.72

GERP RS

0.064

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.017

gMVP

0.39

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