rs200482683
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
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
NM_014625.4 missense
Scores
6
9
4
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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: 18AN: 152216Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000112 AC: 28AN: 250300Hom.: 0 AF XY: 0.0000961 AC XY: 13AN XY: 135256
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GnomAD4 exome AF: 0.000151 AC: 221AN: 1461336Hom.: 0 Cov.: 30 AF XY: 0.000182 AC XY: 132AN XY: 726938
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:15Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
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:5Uncertain: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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at