rs786204583

Positions:

• chr1-179559711-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_014625.4(NPHS2):​c.502C>T​(p.Arg168Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,439,948 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R168H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NPHS2 NM_014625.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.71

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 259) in uniprot entity PODO_HUMAN there are 130 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 chr1-179559710-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 1-179559711-G-A is Pathogenic according to our data. Variant chr1-179559711-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179559711-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.502C>T	p.Arg168Cys	missense_variant	4/8	ENST00000367615.9	NP_055440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9	c.502C>T	p.Arg168Cys	missense_variant	4/8	1	NM_014625.4	ENSP00000356587.4
NPHS2	ENST00000367616.4	c.502C>T	p.Arg168Cys	missense_variant	4/7	1		ENSP00000356588.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1439948 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 714140

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.10e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 2 Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PP3_Strong+PP4 -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 02, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Dr.Nikuei Genetic Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 17, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 04, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 168 of the NPHS2 protein (p.Arg168Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with nephrotic syndrome (PMID: 15253708, 30721404, 32604935). ClinVar contains an entry for this variant (Variation ID: 188952). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPHS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NPHS2 function (PMID: 14675423). This variant disrupts the p.Arg168 amino acid residue in NPHS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14675423, 15042551, 15059485, 26467726, 28385484). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.95		Gain of catalytic residue at L169 (P = 0.0211);Gain of catalytic residue at L169 (P = 0.0211);
MVP		0.93
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.92
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs786204583; hg19: chr1-179528846; COSMIC: COSV62635309; COSMIC: COSV62635309;