rs775006954

Positions:

chr1-179554491-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_014625.4(NPHS2):c.779T>A(p.Val260Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

NPHS2
NM_014625.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 5.49

Variant links:

Genes affected

NPHS2 (HGNC:13394): (NPHS2 stomatin family member, podocin) 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]

NPHS2 links:

AXDND1 (HGNC:26564): (axonemal dynein light chain domain containing 1)

AXDND1 links:

AXDND1 (HGNC:):

AXDND1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 259) in uniprot entity PODO_HUMAN there are 130 pathogenic changes around while only 3 benign (98%) in NM_014625.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

PP5

Variant 1-179554491-A-T is Pathogenic according to our data. Variant chr1-179554491-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 447882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179554491-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS2	NM_014625.4 linkuse as main transcript	c.779T>A	p.Val260Glu	missense_variant	6/8	ENST00000367615.9	NP_055440.1	Q9NP85-1
AXDND1	NM_144696.6 linkuse as main transcript	c.3032-21A>T		intron_variant		ENST00000367618.8	NP_653297.3	Q5T1B0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9 linkuse as main transcript	c.779T>A	p.Val260Glu	missense_variant	6/8	1	NM_014625.4	ENSP00000356587.4		Q9NP85-1
AXDND1	ENST00000367618.8 linkuse as main transcript	c.3032-21A>T		intron_variant		1	NM_144696.6	ENSP00000356590.3		Q5T1B0-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251264

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.000246

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.000338

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:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000869

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephrotic syndrome, type 2

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 05, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000447882, PMID:15253708). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 28658201) and was co-segregated with Nephrotic syndrome, type 2, in multiple affected family members (PP1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.949>=0.6, 3CNET: 0.988>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000317). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 31, 2019	The NPHS2 c.779T>A (p.Val260Glu) variant is a missense variant that has been reported in at least four studies, in which it is found in at least 23 individuals with steroid-resistant nephrotic syndrome, 20 of whom were unrelated. The variant was found in a homozygous state in at least 19 individuals and in a compound heterozygous state with a frameshift variant in another individual (Machuca et al. 2010; Kari et al. 2013; Guaragna et al. 2015; Asharam et al. 2018). The p.Val260Glu variant was found in a heterozygous state in one of 72 controls and is reported at a frequency of 0.000321 in the African population of the Genome Aggregation Database (Asharam et al. 2018). Functional analysis of the p.Val260Glu variant protein in HEK293 cells demonstrated the variant results in retention of podocin in the endoplasmic reticulum in contrast to localization of the wild type protein at the plasma membrane demonstrating a trafficking defect (Roselli et al. 2004). Based on the presence of the variant in affected individuals, functional evidence supporting gene impact, low allele frequency in public frequency databases, and in silico prediction data, the p.Val260Glu variant is classified as pathogenic for steroid-resistant nephrotic syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 10, 2017	Variant summary: The NPHS2 c.779T>A (p.Val260Glu) variant involves the alteration of a conserved nucleotide and results in a replacement of a medium size and hydrophobic Valine (V) with a medium size and polar Glutamine (Q) located in the Band 7 domain of the protein(InterPro). 4/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 2/121340 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS2 variant (0.0017678). It was reported in several nephrotic syndrome patients in homozygosity indicating causality. Moreover, in at least one family, the variant co-segregated with the disease in multiple family members further supporting a pathogenic outcome. A functional study demonstrated the variant to impair localization of NPHS2 to the plasma member ant to result accumulation of the variant in ER accumulation. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 17, 2018	- -
Pathogenic, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Jun 12, 2024	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 260 of the NPHS2 protein (p.Val260Glu). This variant is present in population databases (rs775006954, gnomAD 0.03%). This missense change has been observed in individual(s) with nephrotic syndrome (PMID: 15253708, 28658201). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 447882). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPHS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NPHS2 function (PMID: 14675423). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 13, 2016	- -

Steroid-resistant nephrotic syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

NPHS2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2024

The NPHS2 c.779T>A variant is predicted to result in the amino acid substitution p.Val260Glu. This variant has been reported to be pathogenic for steroid-resistant nephrotic syndrome (SRNS) due to retention of the encoded protein (podocin) in the endoplasmic reticulum (see for example, Weber et al. 2004. PubMed ID: 15253708; Roselli et al. 2004. PubMed ID: 14675423; Bérody et al. 2019. PubMed ID: 29474669). This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

D;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;.

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.85

MVP

0.92

MPC

1.2

ClinPred

0.99

GERP RS

5.4

Varity_R

0.99

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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