rs74315344

Positions:

chr1-179575806-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014625.4(NPHS2):c.59C>T(p.Pro20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,477,634 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0041 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0016 ( 7 hom. )

Consequence

NPHS2
NM_014625.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:13

Conservation

PhyloP100: 1.66

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.059987664).

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS2	NM_014625.4 linkuse as main transcript	c.59C>T	p.Pro20Leu	missense_variant	1/8	ENST00000367615.9	NP_055440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9 linkuse as main transcript	c.59C>T	p.Pro20Leu	missense_variant	1/8	1	NM_014625.4	ENSP00000356587	P1	Q9NP85-1
NPHS2	ENST00000367616.4 linkuse as main transcript	c.59C>T	p.Pro20Leu	missense_variant	1/7	1		ENSP00000356588		Q9NP85-2

Frequencies

GnomAD3 genomes

AF:

0.00410

AC:

623

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00934

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000388

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.00206

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00279

AC:

248

AN:

89040

Hom.:

AF XY:

0.00279

AC XY:

142

AN XY:

50892

show subpopulations

Gnomad AFR exome

AF:

0.0136

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.000235

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00701

Gnomad FIN exome

AF:

0.000351

Gnomad NFE exome

AF:

0.00198

Gnomad OTH exome

AF:

0.00344

GnomAD4 exome

AF:

0.00157

AC:

2084

AN:

1325434

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

1074

AN XY:

653660

show subpopulations

Gnomad4 AFR exome

AF:

0.0107

Gnomad4 AMR exome

AF:

0.00215

Gnomad4 ASJ exome

AF:

0.000285

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00468

Gnomad4 FIN exome

AF:

0.000837

Gnomad4 NFE exome

AF:

0.00113

Gnomad4 OTH exome

AF:

0.00265

GnomAD4 genome

AF:

0.00409

AC:

623

AN:

152200

Hom.:

Cov.:

AF XY:

0.00414

AC XY:

308

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00931

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000390

Gnomad4 SAS

AF:

0.00456

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00206

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00221

Hom.:

Bravo

AF:

0.00437

ESP6500AA

AF:

0.00468

AC:

ESP6500EA

AF:

0.00189

AC:

ExAC

AF:

0.00194

AC:

219

Asia WGS

AF:

0.00231

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nephrotic syndrome, type 2

Pathogenic:1Uncertain:1Benign:3

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2003	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Mar 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	This variant is associated with the following publications: (PMID: 30450462, 23349334, 20947785, 22995991, 10742096, 27884173, 15042551, 26211502, 27885584, 30721404, 28712774) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NPHS2: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2016	Variant summary: The c.59C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Pro to Leu. 2/3 in-silico tools predict this variant to be damaging (SNPs&GO, MutationTaster not captured due to low reliability index). This variant is found in 92/7048 control chromosomes (1 homozygote) at a frequency of 0.0130533, which is about 7 times of maximal expected frequency of a pathogenic allele (0.0017678), suggesting this variant is benign. Although this variant was classified as pathogenic by OMIM via ClinVar, multiple recent literatures suggested this variant was a polymorphism based on the evidence of co-occurrences with a pathogenic variant and homozygous occurrences in controls. Taken together, this variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 25, 2018	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 15, 2024	The p.Pro20Leu variant in NPHS2 is classified as likely benign because it has been identified in 1.0% (57/5542) of Middle Eastern and 0.98% (674/68276) of African/African American chromosomes, including 8 homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0), which is higher than the expected frequency of a pathogenic allele in NPHS2 causing disease. ACMG/AMP Criteria applied: BS1. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	May 10, 2022	- -

Finnish congenital nephrotic syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Vasylyeva lab, Texas Tech University Health Sciences Center

Jan 01, 2019

- -

Steroid-resistant nephrotic syndrome

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jun 11, 2020

- -

NPHS2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Focal segmental glomerulosclerosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.63

T;T

MetaRNN

Benign

0.060

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.6

L;L

MutationTaster

Benign

7.6e-7

A;A

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.2

N;N

REVEL

Uncertain

0.61

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.019

D;D

Polyphen

0.098

B;B

Vest4

0.67

MVP

0.85

MPC

0.27

ClinPred

0.0081

GERP RS

2.8

Varity_R

0.072

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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