NPHS2

NPHS2 stomatin family member, podocin, the group of Stomatin family

Basic information

Region (hg38): 1:179550538-179575952

Links

ENSG00000116218 ∙ NCBI:7827 ∙ OMIM:604766 ∙ HGNC:13394 ∙ Uniprot:Q9NP85 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• nephrotic syndrome, type 2 (Definitive), mode of inheritance: AR
• nephrotic syndrome, type 2 (Definitive), mode of inheritance: AR
• nephrotic syndrome, type 2 (Strong), mode of inheritance: AR
• nephrotic syndrome, type 2 (Definitive), mode of inheritance: AR
• familial idiopathic steroid-resistant nephrotic syndrome (Supportive), mode of inheritance: AD
• nephrotic syndrome, type 2 (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Nephrotic syndrome, type 2	AR	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	Renal	8589695; 8606597; 10742096; 11729243; 12464671; 12707396; 17109732; 22036940; 22080622; 22228437; 22565185; 23013956
The disease is steroid resistant; Partially steroid-responsive AD forms have been described; Renal transplant has been described

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NPHS2 gene.

• not provided (324 variants)
• Nephrotic syndrome, type 2 (174 variants)
• Steroid-resistant nephrotic syndrome (44 variants)
• not specified (26 variants)
• Focal segmental glomerulosclerosis (13 variants)
• Inborn genetic diseases (11 variants)
• Nephrotic syndrome (9 variants)
• Idiopathic nephrotic syndrome (8 variants)
• NPHS2-related condition (7 variants)
• Kidney disorder (3 variants)
• Nephrotic syndrome, type 2, susceptibility to (2 variants)
• Chronic kidney disease (2 variants)
• Finnish congenital nephrotic syndrome (2 variants)
• Nephrotic range proteinuria (2 variants)
• Proteinuria (2 variants)
• Familial idiopathic steroid-resistant nephrotic syndrome (1 variants)
• Corticosteroids response (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NPHS2 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				114	2	116
missense	3	15	62	4		84
nonsense	10	10				20
start loss	2	1				3
frameshift	14	31				45
inframe indel	1	1	6			8
splice donor/acceptor (+/-2bp)	4	17	1			22
splice region		1	1	21	1	24
non coding			11	33	27	71
Total	34	75	80	151	29

Highest pathogenic variant AF is 0.0000131

Variants in NPHS2

This is a list of pathogenic ClinVar variants found in the NPHS2 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-179550745-T-C		Nephrotic syndrome, type 2	Benign (Jan 13, 2018)
1-179550751-A-G		Nephrotic syndrome, type 2	Uncertain significance (Apr 27, 2017)
1-179550833-G-T		Nephrotic syndrome, type 2	Uncertain significance (Jan 13, 2018)
1-179550915-T-C		Nephrotic syndrome, type 2	Benign (Jul 08, 2021)
1-179550964-G-C		Nephrotic syndrome, type 2	Uncertain significance (Jan 12, 2018)
1-179550973-C-T		Nephrotic syndrome, type 2	Benign (Jul 08, 2021)
1-179550974-G-A		Nephrotic syndrome, type 2	Uncertain significance (Jan 13, 2018)
1-179551000-C-T		Nephrotic syndrome, type 2	Uncertain significance (Jan 12, 2018)
1-179551016-C-T		Nephrotic syndrome, type 2	Benign (Jul 08, 2021)
1-179551046-C-G		Nephrotic syndrome, type 2	Uncertain significance (Feb 02, 2018)
1-179551047-G-A		Nephrotic syndrome, type 2	Uncertain significance (Jan 13, 2018)
1-179551119-C-G		Nephrotic syndrome, type 2	Benign (Jul 08, 2021)
1-179551185-A-G			Likely benign (Aug 21, 2022)
1-179551190-CTTTCTT-C		Nephrotic syndrome, type 2	Uncertain significance (May 25, 2018)
1-179551195-T-C			Uncertain significance (Sep 17, 2021)
1-179551198-T-C			Uncertain significance (Sep 17, 2021)
1-179551205-T-A		Nephrotic syndrome	Likely pathogenic (Nov 10, 2017)
1-179551212-C-T		Steroid-resistant nephrotic syndrome	Likely benign (Jan 21, 2024)
1-179551215-A-G			Likely benign (Nov 15, 2022)
1-179551221-T-C			Likely benign (Jan 29, 2023)
1-179551228-G-A		Steroid-resistant nephrotic syndrome	Uncertain significance (Apr 24, 2020)
1-179551239-G-A			Likely benign (Oct 19, 2021)
1-179551242-G-A			Likely benign (Aug 29, 2023)
1-179551242-G-C			Likely benign (Apr 28, 2023)
1-179551245-G-A			Likely benign (Jan 19, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NPHS2	protein_coding	protein_coding	ENST00000367615	8	25414

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
7.22e-9	0.457	125689	0	59	125748	0.000235

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.686	174	201	0.864	0.0000100	2415
Missense in Polyphen		66	75.244	0.87715		934
Synonymous	-0.0811	78	77.1	1.01	0.00000365	800
Loss of Function	0.974	15	19.7	0.763	0.00000116	201

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000429	0.000420
Ashkenazi Jewish	0.00	0.00
East Asian	0.000274	0.000272
Finnish	0.00	0.00
European (Non-Finnish)	0.000265	0.000264
Middle Eastern	0.000274	0.000272
South Asian	0.000398	0.000392
Other	0.000186	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays a role in the regulation of glomerular permeability, acting probably as a linker between the plasma membrane and the cytoskeleton.
• Disease: DISEASE: Nephrotic syndrome 2 (NPHS2) [MIM:600995]: A form of nephrotic syndrome, a renal disease clinically characterized by severe proteinuria, resulting in complications such as hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation. The disorder is resistant to steroid treatment and progresses to end- stage renal failure in the first or second decades. Some patients show later onset of the disorder. {ECO:0000269|PubMed:10742096, ECO:0000269|PubMed:12464671, ECO:0000269|PubMed:15253708, ECO:0000269|PubMed:17899208, ECO:0000269|PubMed:20798252, ECO:0000269|PubMed:20947785, ECO:0000269|PubMed:22565185, ECO:0000269|PubMed:22578956, ECO:0000269|PubMed:23242530, ECO:0000269|PubMed:23800802, ECO:0000269|PubMed:23913389, ECO:0000269|PubMed:24072147, ECO:0000269|PubMed:24227627, ECO:0000269|PubMed:26420286}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Primary Focal Segmental Glomerulosclerosis FSGS;Nephrin/Neph1 signaling in the kidney podocyte (Consensus)

Recessive Scores

• pRec: 0.267

Intolerance Scores

• loftool: 0.251
• rvis_EVS: 0.02
• rvis_percentile_EVS: 55.22

Haploinsufficiency Scores

• pHI: 0.266
• hipred: Y
• hipred_score: 0.661

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.632

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nphs2
• Phenotype: cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); renal/urinary system phenotype; growth/size/body region phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: nphs2
• Affected structure: podocyte
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: excretion;actin cytoskeleton reorganization;metanephric glomerular visceral epithelial cell development
• Cellular component: endoplasmic reticulum;plasma membrane;integral component of plasma membrane;cell-cell junction;intrinsic component of the cytoplasmic side of the plasma membrane;protein-containing complex;slit diaphragm;membrane raft;extracellular exosome
• Molecular function: protein binding