chr1-179557051-C-G
Variant summary
Our verdict is Pathogenic. Variant got 24 ACMG points: 24P and 0B. PS1_Very_StrongPM1PM2PP3_StrongPP5_Very_Strong
The NM_014625.4(NPHS2):c.714G>C(p.Arg238Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,566 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.
Frequency
Consequence
NM_014625.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 24 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPHS2 | NM_014625.4 | c.714G>C | p.Arg238Ser | missense_variant | 5/8 | ENST00000367615.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHS2 | ENST00000367615.9 | c.714G>C | p.Arg238Ser | missense_variant | 5/8 | 1 | NM_014625.4 | P1 | |
NPHS2 | ENST00000367616.4 | c.535-2520G>C | intron_variant | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461566Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727066
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Nephrotic syndrome, type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Steroid-resistant nephrotic syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 20, 2021 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 26, 2019 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A different variant (c.714G>T (p.R238S)) giving rise to the same protein effect observed here (p.Arg238Ser) has been determined to be pathogenic (PMID: 15253708, 15264208, 16810518,23515051, 24072147). This suggests that this variant is also likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with NPHS2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with serine at codon 238 of the NPHS2 protein (p.Arg238Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. - |
Idiopathic nephrotic syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 06, 2023 | Variant summary: NPHS2 c.714G>C (p.Arg238Ser) results in a non-conservative amino acid change located in the Band 7 domain (IPR001107) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250728 control chromosomes. c.714G>C has not been reported in the literature but a different variant, c.714G>T also encoding p.Arg238Ser has been reported in the HGMD database. p.Arg238Ser has been reported in the literature as a biallelic homozygous and compound heterozygous genotype in multiple individuals affected with Steroid Resistant Nephrotic Syndrome, Type 2 (example, PMID: 14675423, 23515051). Therefore, ACMG PS1 criteria - same amino acid change as a previously established pathogenic variant regardless of nucleotide change has been engaged in this ascertainment. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely 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