rs200482683

Positions:

• chr1-179552608-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_014625.4(NPHS2):​c.868G>A​(p.Val290Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,613,552 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: NPHS2 NM_014625.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:15 U:1 O:1
• Conservation: PhyloP100: 2.27

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]

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_014625.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803
• PP5: Variant 1-179552608-C-T is Pathogenic according to our data. Variant chr1-179552608-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126418.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=8, Likely_pathogenic=3, Uncertain_significance=1}. Variant chr1-179552608-C-T is described in Lovd as [Pathogenic]. Variant chr1-179552608-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS2	NM_014625.4	c.868G>A	p.Val290Met	missense_variant	7/8	ENST00000367615.9
AXDND1	NM_144696.6	c.3032-1904C>T		intron_variant		ENST00000367618.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS2	ENST00000367615.9	c.868G>A	p.Val290Met	missense_variant	7/8	1	NM_014625.4	P1
AXDND1	ENST00000367618.8	c.3032-1904C>T		intron_variant		1	NM_144696.6	P2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000112 AC: 28 AN: 250300 Hom.: 0 AF XY: 0.0000961 AC XY: 13 AN XY: 135256

Gnomad AFR exome AF: 0.00

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: 0.0000464

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000151 AC: 221 AN: 1461336 Hom.: 0 Cov.: 30 AF XY: 0.000182 AC XY: 132 AN XY: 726938

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000186

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74378

Gnomad4 AFR AF: 0.00

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: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:15 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nephrotic syndrome, type 2 Pathogenic:9

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Apr 15, 2024	PS4, PM1, PM2, PP3, PP5- The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 126418). Low frequency in gnomAD population databases. It has been previously reported as causative for steroid-resistant nephrotic syndrome (PMID: 11805166, 21171529) -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 11, 2019	The NPHS2 c.868G>A (p.Val290Met) missense variant is reported in six studies in which it is found in a total of 11 individuals affected with steroid-resistant nephrotic syndrome, including in five individuals in a compound heterozygous state, in three affected individuals in a homozygous state and in three individuals in a heterozygous state (Karle et al. 2002; Skálová et al. 2010; Reiterová et al. 2012; Kerti et al. 2013; Lipska et al. 2013; Bińczak-Kuleta et al. 2014). The p.Val290Met variant was absent from 700 control chromosomes and is reported at a frequency of 0.0002412 in the European (non-Finnish) population of the Genome Aggregation Database. Although this variant has been observed in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Based on the collective evidence, the p.Val290Met variant is classified as pathogenic for steroid-resistant nephrotic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 12, 2014	The p.Val290Met variant in NPHS2 has been reported in at least 5 individuals with steroid-resistant nephrotic syndrome. Two individuals were homozygous for this variant (Reiterova 2012, Kerti 2013) and three were compound heterozygotes (Karle 2002, Skalova 2010, Kerti 2013). The variant has been identified in 0.012% (1/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/) Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational analyses (biochemical amino acid properties, conservation, PolyPhen2) do not provide strong support for or against an impact to the protein. In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_014625.2(NPHS2):c.868G>A(V290M) is classified as pathogenic in the context of NPHS2-related nephrotic syndrome. Sources cited for classification include the following: PMID 18216321, 23242530, 21171529, 17899208, 22578956, 11805166 and 14978175. Classification of NM_014625.2(NPHS2):c.868G>A(V290M) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 10, 2016	Variant summary: The NPHS2 c.868G>A (p.Val290Met) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 9/114830 control chromosomes at a frequency of 0.0000784, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS2 variant (0.0017678). This variant has been reported in numerous patients with NSPH2. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:5 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 31589614, 21171529, 33565430, 11805166, 26211502, 24742477, 30295827, 30647093, 24856380, 23242530, 18216321, 31980526, 14978175, 23645318, 17899208, 30586318) -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 290 of the NPHS2 protein (p.Val290Met). This variant is present in population databases (rs200482683, gnomAD 0.03%). This missense change has been observed in individual(s) with NPHS2-related disease (PMID: 11805166, 21171529, 23242530, 24856380, 30295827). 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: 126418). 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 not expected to disrupt NPHS2 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

NPHS2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2022

The NPHS2 c.868G>A variant is predicted to result in the amino acid substitution p.Val290Met. This variant has been reported in the compound heterozygous and homozygous state in individuals with NPHS2-related disease (see for example - Karle et al. 2002. PubMed ID: 11805166; Skálová et al. 2010. PubMed ID: 21171529; Kerti et al. 2012. PubMed ID: 23242530; Table S7 - Groopman et al. 2018. PubMed ID: 30586318; Schapiro et al. 2019. PubMed ID: 30295827; Yao et al. 2019. PubMed ID: 30647093). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-179521743-C-T). This variant is interpreted as pathogenic. -

Nephrotic syndrome, type 2, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	N;N
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.88
MVP		0.79
MPC		0.91
ClinPred		0.32	T
GERP RS		5.3
Varity_R		0.63
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs200482683; hg19: chr1-179521743;