NPRL2

NPR2 like, GATOR1 complex subunit, the group of GATOR1 subcomplex

Basic information

Region (hg38): 3:50347330-50350826

Previous symbols: [ "TUSC4" ]

Links

ENSG00000114388 ∙ NCBI:10641 ∙ OMIM:607072 ∙ HGNC:24969 ∙ Uniprot:Q8WTW4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• epilepsy, familial focal, with variable foci 2 (Moderate), mode of inheritance: AD
• epilepsy, familial focal, with variable foci 2 (Strong), mode of inheritance: AD
• familial focal epilepsy with variable foci (Supportive), mode of inheritance: AD
• familial focal epilepsy with variable foci (Moderate), mode of inheritance: AD
• focal epilepsy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Epilepsy, familial focal, with variable foci 2	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	26505888; 27173016

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NPRL2 gene.

• not provided (2 variants)
• Epilepsy, familial focal, with variable foci 2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NPRL2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	4	1	6
missense		2	43	4		49
nonsense	1	1	1			3
start loss		1				1
frameshift	1	4				5
inframe indel			1			1
splice donor/acceptor (+/-2bp)		1	1			2
splice region		2	2		1	5
non coding		1		2	4	7
Total	2	10	47	10	5

Variants in NPRL2

This is a list of pathogenic ClinVar variants found in the NPRL2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
3-50347546-AC-A		not specified	Benign (Jul 31, 2024)
3-50347609-C-T			Likely benign (Jul 16, 2018)
3-50347638-T-A			Uncertain significance (May 09, 2022)
3-50347667-C-T		Inborn genetic diseases	Uncertain significance (Jul 01, 2022)
3-50347669-C-T		Epilepsy, familial focal, with variable foci 2	Uncertain significance (-)
3-50347755-C-T			Uncertain significance (-)
3-50347777-C-T		Inborn genetic diseases	Uncertain significance (Apr 08, 2024)
3-50347807-G-A		Inborn genetic diseases	Uncertain significance (Jan 20, 2023)
3-50347812-G-A			Uncertain significance (Mar 16, 2022)
3-50347830-C-T		Epilepsy, familial focal, with variable foci 2	Uncertain significance (May 31, 2020)
3-50347839-C-T		Epilepsy, familial focal, with variable foci 2	Uncertain significance (-)
3-50347840-G-A			Uncertain significance (Oct 04, 2022)
3-50347871-G-T			Uncertain significance (-)
3-50347884-C-T			Uncertain significance (May 24, 2021)
3-50347891-G-A			Pathogenic (Nov 01, 2017)
3-50347896-A-C			Uncertain significance (Nov 02, 2019)
3-50347920-G-A		not specified	Likely benign (Apr 10, 2024)
3-50348123-C-T		Epilepsy, familial focal, with variable foci 2	Pathogenic/Likely pathogenic (May 04, 2022)
3-50348124-C-T		NPRL2-related disorder • Epilepsy, familial focal, with variable foci 2	Uncertain significance (Aug 08, 2023)
3-50348145-T-G		Epilepsy, familial focal, with variable foci 2	Uncertain significance (Oct 09, 2019)
3-50348148-TG-T		Familial focal epilepsy with variable foci	Likely pathogenic (-)
3-50348157-C-T		Inborn genetic diseases	Uncertain significance (May 26, 2023)
3-50348172-C-T		Inborn genetic diseases	Uncertain significance (Oct 14, 2021)
3-50348173-G-A		Epilepsy, familial focal, with variable foci 2	Uncertain significance (Aug 29, 2023)
3-50348176-C-T		Inborn genetic diseases	Uncertain significance (Mar 06, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NPRL2	protein_coding	protein_coding	ENST00000232501	11	3762

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.388	0.612	125727	0	13	125740	0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.64	155	224	0.692	0.0000133	2493
Missense in Polyphen		49	82.55	0.59358		873
Synonymous	0.413	84	89.0	0.944	0.00000508	722
Loss of Function	3.40	5	22.4	0.223	0.00000113	251

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000616	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.000278	0.000277
European (Non-Finnish)	0.0000352	0.0000352
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the TORC1 pathway. The GATOR1 complex strongly increases GTP hydrolysis by RRAGA and RRAGB within RRAGC-containing heterodimers, thereby deactivating RRAGs, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling. The GATOR1 complex is negatively regulated by GATOR2 the other GATOR subcomplex in this amino acid-sensing branch of the TORC1 pathway. {ECO:0000269|PubMed:23723238}.
• Disease: DISEASE: Epilepsy, familial focal, with variable foci 2 (FFEVF2) [MIM:617116]: An autosomal dominant form of epilepsy characterized by focal seizures arising from different cortical regions, including the temporal, frontal, parietal, and occipital lobes. Seizure types commonly include temporal lobe epilepsy, frontal lobe epilepsy, and nocturnal frontal lobe epilepsy. Some patients may have intellectual disability or autism spectrum disorders. Seizure onset usually occurs in the first or second decades, although later onset has been reported, and there is phenotypic variability within families. A subset of patients have structural brain abnormalities. Penetrance of the disorder is incomplete. {ECO:0000269|PubMed:26505888, ECO:0000269|PubMed:27173016}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: mTOR signaling pathway - Homo sapiens (human) (Consensus)

Recessive Scores

• pRec: 0.117

Intolerance Scores

• rvis_EVS: -0.43
• rvis_percentile_EVS: 25.15

Haploinsufficiency Scores

• pHI: 0.217
• hipred: Y
• hipred_score: 0.613
• ghis: 0.607

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.824

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Nprl2
• Phenotype: vision/eye phenotype; hematopoietic system phenotype; embryo phenotype; liver/biliary system phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: protein phosphorylation;cellular response to nitrogen starvation;positive regulation of autophagy;negative regulation of TOR signaling;negative regulation of kinase activity;cellular response to amino acid starvation;positive regulation of GTPase activity;regulation of autophagosome assembly
• Cellular component: lysosomal membrane;GATOR1 complex
• Molecular function: protein kinase activity;GTPase activator activity;protein binding