chr1-179575806-G-A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_014625.4(NPHS2):c.59C>T(p.Pro20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,477,634 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_014625.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00410 AC: 623AN: 152092Hom.: 1 Cov.: 34
GnomAD3 exomes AF: 0.00279 AC: 248AN: 89040Hom.: 2 AF XY: 0.00279 AC XY: 142AN XY: 50892
GnomAD4 exome AF: 0.00157 AC: 2084AN: 1325434Hom.: 7 Cov.: 36 AF XY: 0.00164 AC XY: 1074AN XY: 653660
GnomAD4 genome AF: 0.00409 AC: 623AN: 152200Hom.: 1 Cov.: 34 AF XY: 0.00414 AC XY: 308AN XY: 74414
ClinVar
Submissions by phenotype
Nephrotic syndrome, type 2 Pathogenic:1Uncertain:1Benign:3
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
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not provided Benign:5
NPHS2: BS2 -
This variant is associated with the following publications: (PMID: 30450462, 23349334, 20947785, 22995991, 10742096, 27884173, 15042551, 26211502, 27885584, 30721404, 28712774) -
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Variant summary: The c.59C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Pro to Leu. 2/3 in-silico tools predict this variant to be damaging (SNPs&GO, MutationTaster not captured due to low reliability index). This variant is found in 92/7048 control chromosomes (1 homozygote) at a frequency of 0.0130533, which is about 7 times of maximal expected frequency of a pathogenic allele (0.0017678), suggesting this variant is benign. Although this variant was classified as pathogenic by OMIM via ClinVar, multiple recent literatures suggested this variant was a polymorphism based on the evidence of co-occurrences with a pathogenic variant and homozygous occurrences in controls. Taken together, this variant was classified as likely benign. -
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not specified Benign:2
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The p.Pro20Leu variant in NPHS2 is classified as likely benign because it has been identified in 1.0% (57/5542) of Middle Eastern and 0.98% (674/68276) of African/African American chromosomes, including 8 homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0), which is higher than the expected frequency of a pathogenic allele in NPHS2 causing disease. ACMG/AMP Criteria applied: BS1. -
Finnish congenital nephrotic syndrome Uncertain:1
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Steroid-resistant nephrotic syndrome Benign:1
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NPHS2-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Focal segmental glomerulosclerosis Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at