rs776859868

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_014625.4(NPHS2):​c.965G>T​(p.Arg322Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,838 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 Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R322P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NPHS2
NM_014625.4 missense

Scores

14
4
1

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 6.41
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 10 ACMG points.

PM1
In a topological_domain Cytoplasmic (size 259) in uniprot entity PODO_HUMAN there are 133 pathogenic changes around while only 3 benign (98%) in NM_014625.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-179551361-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3574218.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPHS2NM_014625.4 linkc.965G>T p.Arg322Leu missense_variant Exon 8 of 8 ENST00000367615.9 NP_055440.1 Q9NP85-1
AXDND1NM_144696.6 linkc.3032-3152C>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.965G>T p.Arg322Leu missense_variant Exon 8 of 8 1 NM_014625.4 ENSP00000356587.4 Q9NP85-1
AXDND1ENST00000367618.8 linkc.3032-3152C>A intron_variant Intron 25 of 25 1 NM_144696.6 ENSP00000356590.3 Q5T1B0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251048
Hom.:
0
AF XY:
0.00000737
AC XY:
1
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461838
Hom.:
0
Cov.:
42
AF XY:
0.00000138
AC XY:
1
AN XY:
727218
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

NPHS2-related disorder Uncertain:1
Jul 28, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The NPHS2 c.965G>T variant is predicted to result in the amino acid substitution p.Arg322Leu. To our knowledge, this variant has not been reported in the literature. However, other amino acid substitutions at this position have been reported in individuals with nephrotic syndrome (p.Arg322Gln in Berdeli et al. 2007. PubMed ID: 17899208; p.Arg322Pro in Sharma et al. 2008. PubMed ID: 19484379; p.Arg322Gly in Basiratnia et al. 2013. PubMed ID: 24072147). The c.965G>T (p.Arg322Leu) variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.66
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;.
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Pathogenic
4.1
H;.
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-6.7
D;D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.95
MutPred
0.74
Loss of methylation at R322 (P = 0.0537);.;
MVP
0.91
MPC
1.0
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.76
gMVP
0.93

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: rs776859868; hg19: chr1-179520495; API