1-179559745-CA-CAA

Position:

• chr1-179559745-CA-CAA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_014625.4(NPHS2):​c.467dupT​(p.Leu156fs) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:2
• Conservation: PhyloP100: 6.96

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]

ACMG classification

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=10}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.467dupT	p.Leu156fs	frameshift_variant	4/8	ENST00000367615.9	NP_055440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9	c.467dupT	p.Leu156fs	frameshift_variant	4/8	1	NM_014625.4	ENSP00000356587.4
NPHS2	ENST00000367616.4	c.467dupT	p.Leu156fs	frameshift_variant	4/7	1		ENSP00000356588.4

Frequencies

GnomAD3 genomes AF: 0.0000464 AC: 7 AN: 150806 Hom.: 0 Cov.: 32

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: 73 AN: 1423766 Hom.: 0 Cov.: 30 AF XY: 0.0000468 AC XY: 33 AN XY: 705762

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: 6 AN: 150924 Hom.: 0 Cov.: 32 AF XY: 0.0000543 AC XY: 4 AN XY: 73634

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:13 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nephrotic syndrome, type 2 Pathogenic:10 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 27, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 07, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	May 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -
Pathogenic, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Precision Medicine Center, Zhengzhou University	Dec 01, 2023	PVS1,PM2_p,PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 06, 2024	- -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	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. -

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

May 13, 2024

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

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

Other links and lift over

dbSNP: rs528833893; hg19: chr1-179528880;