1-179551361-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_014625.4(NPHS2):​c.964C>T​(p.Arg322*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000124 in 1,613,992 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R322R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

NPHS2
NM_014625.4 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.00
Variant links:
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]
AXDND1 (HGNC:26564): (axonemal dynein light chain domain containing 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 21 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-179551361-G-A is Pathogenic according to our data. Variant chr1-179551361-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179551361-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPHS2NM_014625.4 linkc.964C>T p.Arg322* stop_gained Exon 8 of 8 ENST00000367615.9 NP_055440.1 Q9NP85-1
AXDND1NM_144696.6 linkc.3032-3151G>A intron_variant Intron 25 of 25 ENST00000367618.8 NP_653297.3 Q5T1B0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPHS2ENST00000367615.9 linkc.964C>T p.Arg322* stop_gained Exon 8 of 8 1 NM_014625.4 ENSP00000356587.4 Q9NP85-1
AXDND1ENST00000367618.8 linkc.3032-3151G>A intron_variant Intron 25 of 25 1 NM_144696.6 ENSP00000356590.3 Q5T1B0-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251050
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135638
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461846
Hom.:
0
Cov.:
43
AF XY:
0.0000193
AC XY:
14
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Nephrotic syndrome, type 2 Pathogenic:5
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsNov 20, 2023- -
Likely pathogenic, criteria provided, single submitterclinical testingCounsylNov 14, 2016- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJun 30, 2021- -
Likely pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The observed stop gained variant c.964C>T(p.Arg322Ter) in NPHS2 gene has been reported in compound heteroygous state in an individual with steroid-resistant nephrotic syndrome (Weber S, et al., 2004). This variant disrupts a region of the NPHS2 protein in which other variant(s) (p.Phe344Leufs*4) have been determined to be pathogenic (Lipska BS, et al., 2013). The c.964C>T(p.Arg322Ter) variant is reported with 0.0004% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The nucleotide change c.964C>T in NPHS2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence (Mutation Taster - Disease causing) predicts damaging effect on protein structure and function for this variant.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 -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 02, 2022For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NPHS2 protein in which other variant(s) (p.Phe344Leufs*4) have been determined to be pathogenic (PMID: 23515051, 29660491; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 371673). This premature translational stop signal has been observed in individual(s) with steroid-resistant nephrotic syndrome (PMID: 15253708). This variant is present in population databases (rs763818901, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg322*) in the NPHS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 62 amino acid(s) of the NPHS2 protein. -
Idiopathic nephrotic syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 09, 2023Variant summary: NPHS2 c.964C>T (p.Arg322X) 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 associated with Nephrotic Syndrome in HGMD. The variant allele was found at a frequency of 4e-06 in 251370 control chromosomes. c.964C>T has been reported in the literature in one individual affected with sporadic steroid-resistant nephrotic syndrome (Weber_2004). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
43
DANN
Uncertain
0.99
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.83
D
Vest4
0.96
GERP RS
4.8

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs763818901; hg19: chr1-179520496; COSMIC: COSV62636639; COSMIC: COSV62636639; API