rs776859868

Variant names:

Your query was ambiguous. Multiple possible variants found:

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

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]

NPHS2 links:

AXDND1 (HGNC:26564): (axonemal dynein light chain domain containing 1)

AXDND1 links:

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
NPHS2	NM_014625.4 link	c.965G>T	p.Arg322Leu	missense_variant	Exon 8 of 8	ENST00000367615.9	NP_055440.1	Q9NP85-1
AXDND1	NM_144696.6 link	c.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
NPHS2	ENST00000367615.9 link	c.965G>T	p.Arg322Leu	missense_variant	Exon 8 of 8	1	NM_014625.4	ENSP00000356587.4		Q9NP85-1
AXDND1	ENST00000367618.8 link	c.3032-3152C>A		intron_variant	Intron 25 of 25	1	NM_144696.6	ENSP00000356590.3		Q5T1B0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251048

Hom.:

AF XY:

0.00000737

AC XY:

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:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

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.:

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

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.1

H;.

PrimateAI

Uncertain

0.60

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over