1-179559745-CA-CAA
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_014625.4(NPHS2):c.467_468insT(p.Leu156PhefsTer11) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000502 in 1,574,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000051 ( 0 hom. )
Consequence
NPHS2
NM_014625.4 frameshift
NM_014625.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.96
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-179559745-C-CA is Pathogenic according to our data. Variant chr1-179559745-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 556941.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=9, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPHS2 | NM_014625.4 | c.467_468insT | p.Leu156PhefsTer11 | frameshift_variant | 4/8 | ENST00000367615.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHS2 | ENST00000367615.9 | c.467_468insT | p.Leu156PhefsTer11 | frameshift_variant | 4/8 | 1 | NM_014625.4 | P1 | |
NPHS2 | ENST00000367616.4 | c.467_468insT | p.Leu156PhefsTer11 | frameshift_variant | 4/7 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000464 AC: 7AN: 150806Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
7
AN:
150806
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.0000513 AC: 73AN: 1423766Hom.: 0 Cov.: 30 AF XY: 0.0000468 AC XY: 33AN XY: 705762
GnomAD4 exome
AF:
AC:
73
AN:
1423766
Hom.:
Cov.:
30
AF XY:
AC XY:
33
AN XY:
705762
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000398 AC: 6AN: 150924Hom.: 0 Cov.: 32 AF XY: 0.0000543 AC XY: 4AN XY: 73634
GnomAD4 genome
?
AF:
AC:
6
AN:
150924
Hom.:
Cov.:
32
AF XY:
AC XY:
4
AN XY:
73634
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:10Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Nephrotic syndrome, type 2 Pathogenic:8Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The frameshift c.467dup p.Leu156PhefsTer11 variant in NPHS2 gene has been reported previously in both homozygous and compound heterozygous state in individuals affected with nephrotic syndrome Wang et al. 2017; Shi et al. 2021. The p.Leu156PhefsTer11 variant is reported with an allele frequency of 0.02% in the gnomAD exomes database and is novel not in any individuals in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic multiple submissions. This variant causes a frameshift starting with codon Leucine 156, changes this amino acid to Phenylalanine residue, and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Leu156PhefsTer11. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 02, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 11, 2017 | Variant summary: The NPHS2 c.467dupT (p.Leu156PhefsX11) variant results in a premature termination codon, predicted to cause a truncated or absent NPHS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 42/199282 control chromosomes at a frequency of 0.0002108, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS2 variant (0.0017678). This variant has been reported in multiple patients with steroid-resistant nephrotic syndrome and classified as pathogenic by a reputable database. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 27, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.021%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with NPHS2 related disorder (ClinVar ID: VCV000556941 / PMID: 11729243). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | May 08, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 07, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Pathogenic, criteria provided, single submitter | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change creates a premature translational stop signal (p.Leu156Phefs*11) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with steroid-resistant nephrotic syndrome or focal segmental glomerulosclerosis (PMID: 11729243, 19674119, 25903641, 28204945). ClinVar contains an entry for this variant (Variation ID: 556941). For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 26, 2020 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28780565, 28204945, 19674119, 25903641, 15338398, 11729243, 15059485, 30295827, 31209189, 33428103) - |
Steroid-resistant nephrotic syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at