rs769961301

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006545.5(NPRL2):ā€‹c.932G>Cā€‹(p.Arg311Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

NPRL2
NM_006545.5 missense, splice_region

Scores

10
7
2
Splicing: ADA: 1.000
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.84
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPRL2NM_006545.5 linkc.932G>C p.Arg311Pro missense_variant, splice_region_variant Exon 9 of 11 ENST00000232501.8 NP_006536.3 Q8WTW4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPRL2ENST00000232501.8 linkc.932G>C p.Arg311Pro missense_variant, splice_region_variant Exon 9 of 11 1 NM_006545.5 ENSP00000232501.3 Q8WTW4-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251092
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135742
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:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461522
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727058
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:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.62
D
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D
M_CAP
Benign
0.075
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Uncertain
0.30
D
MutationAssessor
Pathogenic
3.1
M
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-6.0
D
REVEL
Pathogenic
0.85
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0040
D
Polyphen
1.0
D
Vest4
0.92
MutPred
0.85
Gain of loop (P = 0.0045);
MVP
0.69
MPC
1.8
ClinPred
0.99
D
GERP RS
5.7
Varity_R
0.94
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.75
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.75
Position offset: 0

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: rs769961301; hg19: chr3-50385555; API