rs74315345

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_014625.4(NPHS2):​c.274G>T​(p.Gly92Cys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G92S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

NPHS2
NM_014625.4 missense, splice_region

Scores

8
8
3
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.33

Publications

15 publications found
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]
NPHS2 Gene-Disease associations (from GenCC):
  • nephrotic syndrome, type 2
    Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, G2P
  • familial idiopathic steroid-resistant nephrotic syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.68612 (below the threshold of 3.09). Trascript score misZ: 0.038296 (below the threshold of 3.09). GenCC associations: The gene is linked to nephrotic syndrome, type 2, familial idiopathic steroid-resistant nephrotic syndrome.
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 1-179575591-C-A is Pathogenic according to our data. Variant chr1-179575591-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 5366.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPHS2NM_014625.4 linkc.274G>T p.Gly92Cys missense_variant, splice_region_variant Exon 1 of 8 ENST00000367615.9 NP_055440.1 Q9NP85-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPHS2ENST00000367615.9 linkc.274G>T p.Gly92Cys missense_variant, splice_region_variant Exon 1 of 8 1 NM_014625.4 ENSP00000356587.4 Q9NP85-1
NPHS2ENST00000367616.4 linkc.274G>T p.Gly92Cys missense_variant, splice_region_variant Exon 1 of 7 1 ENSP00000356588.4 Q9NP85-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00209
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Nephrotic syndrome, type 2 Pathogenic:1
Apr 01, 2000
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
35
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.77
D;.
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.83
T;T
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.4
M;M
PhyloP100
4.3
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-3.7
D;D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.91
MutPred
0.77
Loss of disorder (P = 0.0425);Loss of disorder (P = 0.0425);
MVP
0.95
MPC
0.94
ClinPred
1.0
D
GERP RS
4.1
PromoterAI
-0.14
Neutral
Varity_R
0.80
gMVP
0.84
Mutation Taster
=2/98
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.95
SpliceAI score (max)
0.52
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.52
Position offset: -36

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

Publications

Other links and lift over

dbSNP: rs74315345; hg19: chr1-179544726; COSMIC: COSV62635220; COSMIC: COSV62635220; API