GeneBe

NPHS2

protein-coding

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

Gene summary

This gene encodes a protein that plays a role in the regulation of glomerular permeability. Mutations in this gene cause steroid-resistant nephrotic syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MANE transcript

NM_014625.4

Inheritance

AR, AD

ClinVar variants

P:180U:145B:167

Top phenotype

Nephrotic syndrome, type 2

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr1:179,550,539-179,575,952

External References & Databases

Ensembl (ENSG00000116218)NCBI Gene (7827)OMIM (604766)HGNC:13394GenCCUniProt (Q9NP85)AlphaFoldClinVar (NPHS2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~25.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nephrotic syndrome, type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010974

Submitter: Illumina

The NPHS2 gene is located on chromosome 1 at 1q25.2 and encodes NPHS2 stomatin family member, podocin. Podocin is expressed in the kidney, specifically in podocytes of glomeruli where it is localised at the slit diaphragm. Podocin interacts with nephrin and mediates glomerular permeability and filtration and plays a role in podocyte cell signaling. NPHS2 was first reported in relation to autosomal recessive nephrotic syndrome in 2000 (10742096: Boute et al. 2000). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least eight unique variants have been reported in seven probands with nephrotic syndrome from three studies in the literature (10742096: Boute et al. 2000; 23242530: Kerti et al. 2013; 17371932: Hinkes et al. 2007). These included two missense variants, a nonsense variant and four small indels resulting in frameshift. Variants in this gene segregated with disease in at least five additional family members across three families. More genetic evidence is available in the literature, but the maximum score for this category has been reached. The mechanism for disease is loss of function. This gene-disease relationship is supported by the specific expression of podocin in the glomeruli of the kidney (10742096: Boute et al. 2000), demonstration of interaction of with nephrin (variants in which are also known to cause nephrotic syndrome) (14570703: Huber et al. 2003), and a mouse model which recapitulates clinical and histological features of the disease (29049388: Tabatabaeifar et al. 2017). In summary, NPHS2 is definitively associated with nephrotic syndrome.

nephrotic syndrome, type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010974

Submitter: Labcorp Genetics (formerly Invitae)

nephrotic syndrome, type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010974

Submitter: Myriad Women's Health

familial idiopathic steroid-resistant nephrotic syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019006

Submitter: Orphanet

nephrotic syndrome, type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010974

Submitter: Natera

nephrotic syndrome, type 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0010974

Submitter: Ambry Genetics

nephrotic syndrome, type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010974

Submitter: G2P

nephrotic syndrome, type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010974

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Nephrotic syndrome, type 2AR

Manifestation: Renal

Intervention: General

Rationale: 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

Comments: The disease is steroid resistant; Partially steroid-responsive AD forms have been described; Renal transplant has been described

Refs: 8589695; 8606597; 10742096; 11729243; 12464671; 12707396; 17109732; 22036940; 22080622; 22228437; 22565185; 23013956Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NPHS2 variants in ClinVar

18 Conditions Cataloged
not providedTotal: 391
Nephrotic syndrome, type 2Total: 247
Steroid-resistant nephrotic syndromeTotal: 107
not specifiedTotal: 35
NPHS2-related disorderTotal: 34
Inborn genetic diseasesTotal: 31
Nephrotic syndromeTotal: 13
Focal segmental glomerulosclerosisTotal: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014625.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
8
clinvar
159
clinvar
1
clinvar
 168
missense
7
clinvar
37
clinvar
134
clinvar
5
clinvar
2
clinvar
 185
nonsense
12
clinvar
17
clinvar
 29
start loss
2
clinvar
2
clinvar
 4
frameshift
29
clinvar
48
clinvar
2
clinvar
 79
splice donor/acceptor (+/-2bp)
4
clinvar
22
clinvar
1
clinvar
 27
Total541261451643492

Highest pathogenic variant AF is 0.0007972158

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_014625.4RefSeqNP_055440.18MANE Select
ENST00000367615.9EnsemblENSP00000356587.48MANE Select
NM_001297575.2RefSeqNP_001284504.17Standard
ENST00000367616.4EnsemblENSP00000356588.47Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
nphs2Danio rerio

Structure: podocyte

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Primary Focal Segmental Glomerulosclerosis FSGS
  • Nephrin/Neph1 signaling in the kidney podocyte

Biological Process

  • excretion
  • actin cytoskeleton reorganization
  • metanephric glomerular visceral epithelial cell development

Molecular Function

  • protein binding

Cellular Component

  • endoplasmic reticulum
  • plasma membrane
  • integral component of plasma membrane
  • cell-cell junction
  • intrinsic component of the cytoplasmic side of the plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000367615
Coding exons
8
Length
25414
Individuals with no LoFs
125689
Homozygous LoFs
0
Heterozygous LoFs
59
Defined
125748
p
0.000235
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.6861742010.8640.00001002415
Missense (PolyPhen)6675.2440.87715934
Synonymous-0.08117877.11.010.00000365800
Loss of Function0.9741519.70.7630.00000116201

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000190.00018rare
Latino/Admixed American0.000240.00023rare
Ashkenazi Jewish00.0absent
East Asian0.000270.00027rare
Finnish00.0absent
European (Non-Finnish)0.000260.00026rare
South Asian0.000400.00039rare
Other0.000190.00016rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.267

Intolerance Scores

LoFtool
0.251
RVIS EVS
0.02
RVIS percentile EVS
55.22

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.632

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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