Variant 3-50347667-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_006545.5(NPRL2):c.1082G>A(p.Ser361Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000471 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

NPRL2
NM_006545.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.42

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 -4 ACMG points.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NPRL2	NM_006545.5 linkuse as main transcript	c.1082G>A	p.Ser361Asn	missense_variant	11/11	ENST00000232501.8	NP_006536.3
NPRL2	XM_047447310.1 linkuse as main transcript	c.1160G>A	p.Ser387Asn	missense_variant	11/11		XP_047303266.1
NPRL2	XM_011533288.4 linkuse as main transcript	c.1073G>A	p.Ser358Asn	missense_variant	10/10		XP_011531590.1
NPRL2	XM_017005556.3 linkuse as main transcript	c.722G>A	p.Ser241Asn	missense_variant	9/9		XP_016861045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPRL2	ENST00000232501.8 linkuse as main transcript	c.1082G>A	p.Ser361Asn	missense_variant	11/11	1	NM_006545.5	ENSP00000232501	P1	Q8WTW4-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251376

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135884

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:

0.0000479

AC:

AN:

1461772

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727164

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000576

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.1082G>A (p.S361N) alteration is located in exon 11 (coding exon 11) of the NPRL2 gene. This alteration results from a G to A substitution at nucleotide position 1082, causing the serine (S) at amino acid position 361 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

NPRL2: PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.071

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.84

M_CAP

Benign

0.0096

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.6

REVEL

Benign

0.19

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.020

Polyphen

0.17

Vest4

0.52

MutPred

0.91

Loss of ubiquitination at K357 (P = 0.0863);

MVP

0.54

MPC

1.1

ClinPred

0.75

GERP RS

4.9

Varity_R

0.49

gMVP

0.64

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