rs74315343
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014625.4(NPHS2):c.412C>T(p.Arg138Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,612,836 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R138R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_014625.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPHS2 | NM_014625.4 | c.412C>T | p.Arg138Ter | stop_gained | 3/8 | ENST00000367615.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHS2 | ENST00000367615.9 | c.412C>T | p.Arg138Ter | stop_gained | 3/8 | 1 | NM_014625.4 | P1 | |
NPHS2 | ENST00000367616.4 | c.412C>T | p.Arg138Ter | stop_gained | 3/7 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151938Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251298Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135822
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1460898Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8AN XY: 726824
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151938Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74188
ClinVar
Submissions by phenotype
Nephrotic syndrome, type 2 Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gained p.R138* in NPHS2 (NM_014625.4) has been reported previously in individual(s) with nephrotic syndrome (Boute et al, 2000). The p.R138* variant has a GnomAD frequency of 0.001592 % and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. The p.R138* variant is a loss of function variant in the gene NPHS2, which is intolerant of Loss of Function variants. The nucleotide change in NPHS2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates.For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Molecular Biology Laboratory, Fundació Puigvert | Feb 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 04, 2019 | NM_014625.2(NPHS2):c.412C>T(R138*) is classified as pathogenic in the context of NPHS2-related nephrotic syndrome. Sources cited for classification include the following: PMID 17899208, 11805168, 20798252, 10742096 and 14570703. Classification of NM_014625.2(NPHS2):c.412C>T(R138*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 21, 2024 | - - |
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The heterozygous p.Arg138Ter variant in NPHS2 was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with nephrotic syndrome. This variant has also been reported pathogenic in ClinVar (Variation ID: 5361). The p.Arg138Ter variant in NPHS2 has been reported in 15 Arab-Israeli individuals with nephrotic syndrome, segregated with disease in 9 affected relatives from 2 families (PMID: 11805168), and has been identified in 0.006538% (1/15296) of African chromosomes, 0.002979% (1/33564) of Latino chromosomes, and 0.001792% (2/111604) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs74315343). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 138, which is predicted to lead to a truncated or absent protein. Loss of function of the NPHS2 gene is an established disease mechanism in autosomal recessive nephrotic syndrome. The presence of this variant in combination with a pathogenic variant reported in this study and in an individual with nephrotic syndrome increases the likelihood that the p.Arg138Ter variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for nephrotic syndrome in an autosomal recessive manner based on the predicted impact of the variant and cosegration with disease in multiple families. ACMG/AMP Criteria applied: PM2, PVS1, PP1_Moderate, PM3 (Richards 2015). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2007 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 31, 2019 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Strong co-segregation with disease in affected and unaffected individuals, but from a single family. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2023 | This sequence change creates a premature translational stop signal (p.Arg138*) 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). This variant is present in population databases (rs74315343, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with nephrotic syndrome (PMID: 10742096). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5361). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NPHS2 function (PMID: 14570703). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 | - - |
Focal segmental glomerulosclerosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Sep 06, 2022 | - - |
Idiopathic nephrotic syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 01, 2022 | Variant summary: NPHS2 c.412C>T (p.Arg138X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 251298 control chromosomes (gnomAD). c.412C>T has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 2 (e.g. Boute_2000, Frishberg_2006). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant results in the loss of both homo-oligomerization and interaction with nephrin (Huber_2003). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at