Genetic Variant NPHS2:p.Leu156PhefsTer11 (chr1-179559745-C-CA) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_014625.4(NPHS2):c.467dupT(p.Leu156PhefsTer11) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000502 in 1,574,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

NPHS2
NM_014625.4 frameshift

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 6.96

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 Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-179559745-C-CA is Pathogenic according to our data. Variant chr1-179559745-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 556941.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=11}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4 link	c.467dupT	p.Leu156PhefsTer11	frameshift_variant	Exon 4 of 8	ENST00000367615.9	NP_055440.1	Q9NP85-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9 link	c.467dupT	p.Leu156PhefsTer11	frameshift_variant	Exon 4 of 8	1	NM_014625.4	ENSP00000356587.4		Q9NP85-1
NPHS2	ENST00000367616.4 link	c.467dupT	p.Leu156PhefsTer11	frameshift_variant	Exon 4 of 7	1		ENSP00000356588.4		Q9NP85-2

Frequencies

GnomAD3 genomes

AF:

0.0000464

AC:

AN:

150806

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000488

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000210

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.000484

GnomAD4 exome

AF:

0.0000513

AC:

AN:

1423766

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

705762

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.0000395

Gnomad4 EAS exome

AF:

0.000104

Gnomad4 SAS exome

AF:

0.000109

Gnomad4 FIN exome

AF:

0.0000777

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.0000511

GnomAD4 genome

AF:

0.0000398

AC:

AN:

150924

Hom.:

Cov.:

AF XY:

0.0000543

AC XY:

AN XY:

73634

show subpopulations

Gnomad4 AFR

AF:

0.0000487

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000211

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000567

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nephrotic syndrome, type 2

Pathogenic:10Uncertain:1

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift c.467dup p.Leu156PhefsTer11 variant in NPHS2 gene has been reported previously in both homozygous and compound heterozygous state in individuals affected with nephrotic syndrome Wang et al. 2017; Shi et al. 2021. The p.Leu156PhefsTer11 variant is reported with an allele frequency of 0.02% in the gnomAD exomes database and is novel not in any individuals in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic multiple submissions. This variant causes a frameshift starting with codon Leucine 156, changes this amino acid to Phenylalanine residue, and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Leu156PhefsTer11. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Dec 01, 2023

Precision Medicine Center, Zhengzhou University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1,PM2_p,PP4 -

Feb 27, 2018

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2017

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 08, 2019

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.021%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with NPHS2 related disorder (ClinVar ID: VCV000556941 / PMID: 11729243). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 21, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The NPHS2 c.467dupT (p.Leu156PhefsX11) variant results in a premature termination codon, predicted to cause a truncated or absent NPHS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 42/199282 control chromosomes at a frequency of 0.0002108, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS2 variant (0.0017678). This variant has been reported in multiple patients with steroid-resistant nephrotic syndrome and classified as pathogenic by a reputable database. Taken together, this variant is classified as pathogenic. -

not provided

Pathogenic:1Uncertain:1

Jul 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu156Phefs*11) in the NPHS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS2 are known to be pathogenic (PMID: 10742096, 14701729, 15253708, 23595123). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with steroid-resistant nephrotic syndrome or focal segmental glomerulosclerosis (PMID: 11729243, 19674119, 25903641, 28204945). ClinVar contains an entry for this variant (Variation ID: 556941). For these reasons, this variant has been classified as Pathogenic. -

Jun 26, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28780565, 28204945, 19674119, 25903641, 15338398, 11729243, 15059485, 30295827, 31209189, 33428103) -

Steroid-resistant nephrotic syndrome

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

NPHS2-related disorder

Pathogenic:1

May 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NPHS2 c.467dupT variant is predicted to result in a frameshift and premature protein termination (p.Leu156Phefs*11). This variant was reported in multiple individuals with autosomal recessive nephrotic syndrome (Caridi et al. 2001. PubMed ID: 11729243; Klaassen et al. 2015. PubMed ID: 25903641; Saeed et al. 2021. PubMed ID: 33565430; Table S1, Zhu et al. 2022. PubMed ID: 35755072). This variant is reported in 0.057% of alleles in individuals of African descent in gnomAD. Frameshift variants in NPHS2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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