rs869025495
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_014625.4(NPHS2):c.353C>T(p.Pro118Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,830 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P118S) has been classified as Uncertain significance.
Frequency
Consequence
NM_014625.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPHS2 | NM_014625.4 | c.353C>T | p.Pro118Leu | missense_variant | 2/8 | ENST00000367615.9 | NP_055440.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPHS2 | ENST00000367615.9 | c.353C>T | p.Pro118Leu | missense_variant | 2/8 | 1 | NM_014625.4 | ENSP00000356587.4 | ||
NPHS2 | ENST00000367616.4 | c.353C>T | p.Pro118Leu | missense_variant | 2/7 | 1 | ENSP00000356588.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461830Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727222
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Nephrotic syndrome, type 2 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 11, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Oct 12, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 27, 2024 | - - |
Proteinuria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 28, 2015 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 21, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 118 of the NPHS2 protein (p.Pro118Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of nephrotic syndrome (PMID: 15253708, 15264208). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 222762). 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%. Experimental studies have shown that this missense change affects NPHS2 function (PMID: 14675423, 24596097). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at