rs61747728

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is . The variant received 0 classification points (ACMG Germline Pathogenicity v2019): 4P and 4B. PS3BS1

The NM_014625.4(NPHS2):c.686G>A (p.Arg229Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0348 (AC=56,130) in the gnomAD database across 1,613,872 control chromosomes, including 1,141 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0373. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars). ClinVar reports functional evidence for this variant: "SCV002767976: "This variant has moderate functional evidence supporting abnormal protein function. Functional analysis showed NPHS2-R229Q had reduced binding with NPHS1 (PMID:12464671). Co-expression of NPHS2-R229Q and NPHS2 with different pathogenic missense variants showed the proteins were mislocalised (PMID:24509478)."" and additional evidence is available in ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R229= (synonymous): Conflicting_classifications_of_pathogenicity (ClinVar VariationId 1160562) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

Frequency

Genomes: 𝑓 0.028 ( 85 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1056 hom. )

Consequence

NPHS2
NM_014625.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16U:12B:1O:2

Conservation

PhyloP100: 2.46

Publications

179 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: PanelApp Australia, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P, Myriad Women's Health
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NPHS2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_014625.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 points.

PS3

Well-established functional study supports damaging effect (PS3); SCV002767976: "This variant has moderate functional evidence supporting abnormal protein function. Functional analysis showed NPHS2-R229Q had reduced binding with NPHS1 (PMID: 12464671). Co-expression of NPHS2-R229Q and NPHS2 with different pathogenic missense variants showed the proteins were mislocalised (PMID: 24509478)."; SCV004175662: Transfection studies in human podocyte cell lines showed that when the p.Ala297Val variant was co-expressed with p.Arg229Gln (also in this patient), podocin was retained in the cytoplasm, rather than localising properly to the plasma membrane (Tory et al. 2014 PMID:24509478) (PS3).; SCV006080908: Functional studies using podocites have shown that this change alters the expression of the protein (PMID:24509478;12464671).; SCV000842933: Experiments demonstrate this variant results in reduced binding of podocin to nephrin (PMID: 12464671, 24509478).; SCV004056463: Functional analysis demonstrated decreased nephrin binding to the p.R229Q podocin compared to the wild type (Tsukaguchi, 2002). Additional functional studies suggest that this alteration is pathogenic when in trans with certain NPHS2 mutations due to altered heterodimerization and mislocalization of the encoded p.R229Q podocin (Tory, 2014).

BS1

GnomAD effective popmax AF above BS1 threshold — greater than expected for disorder; GnomAD AF = 0.0373 exceeds threshold, but 14 reliable P/LP ClinVar submissions — likely a high-frequency founder pathogenic allele; BS1 blocked.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_014625.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	NM_014625.4	MANE Select	c.686G>A	p.Arg229Gln	missense	Exon 5 of 8	NP_055440.1	Q9NP85-1
	NPHS2	NM_001297575.2		c.535-2548G>A		intron	N/A	NP_001284504.1	Q9NP85-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPHS2	ENST00000367615.9	TSL:1 MANE Select	c.686G>A	p.Arg229Gln	missense	Exon 5 of 8	ENSP00000356587.4	Q9NP85-1
NPHS2	ENST00000367616.4	TSL:1	c.535-2548G>A		intron	N/A	ENSP00000356588.4	Q9NP85-2
NPHS2	ENST00000902256.1		c.509G>A	p.Arg170Gln	missense	Exon 3 of 6	ENSP00000572315.1

Frequencies

GnomAD3 genomes

AF:

0.0277

AC:

4222

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00611

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.0187

Gnomad ASJ

AF:

0.0565

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0281

Gnomad FIN

AF:

0.0664

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0374

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.0304

AC:

7639

AN:

250894

AF XY:

0.0313

show subpopulations

Gnomad AFR exome

AF:

0.00621

Gnomad AMR exome

AF:

0.0128

Gnomad ASJ exome

AF:

0.0524

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0697

Gnomad NFE exome

AF:

0.0358

Gnomad OTH exome

AF:

0.0295

GnomAD4 exome

AF:

0.0355

AC:

51908

AN:

1461584

Hom.:

1056

Cov.:

AF XY:

0.0356

AC XY:

25877

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.00574

AC:

192

AN:

33478

American (AMR)

AF:

0.0140

AC:

626

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0485

AC:

1267

AN:

26132

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39686

South Asian (SAS)

AF:

0.0280

AC:

2415

AN:

86242

European-Finnish (FIN)

AF:

0.0661

AC:

3527

AN:

53374

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0376

AC:

41780

AN:

1111840

Other (OTH)

AF:

0.0331

AC:

2000

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

2523

5046

7569

10092

12615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1574

3148

4722

6296

7870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0277

AC:

4222

AN:

152288

Hom.:

Cov.:

AF XY:

0.0284

AC XY:

2112

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00609

AC:

253

AN:

41556

American (AMR)

AF:

0.0186

AC:

285

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0565

AC:

196

AN:

3468

East Asian (EAS)

AF:

0.000385

AC:

AN:

5192

South Asian (SAS)

AF:

0.0282

AC:

136

AN:

4830

European-Finnish (FIN)

AF:

0.0664

AC:

704

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0374

AC:

2543

AN:

68022

Other (OTH)

AF:

0.0199

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

210

420

631

841

1051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0316

Hom.:

224

Bravo

AF:

0.0232

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.0356

EpiControl

AF:

0.0352

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0000650

AC:

AN:

122764

Turkish Variome

AF:

0.0296

AC:

199

AN:

6724

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.000112

AC:

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.0235

AC:

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nephrotic syndrome, type 2 (17)

not provided (6)

not specified (2)

Inborn genetic diseases (1)

Nephrotic syndrome (2)

NPHS2-related disorder (1)

Proteinuria (1)

NEPHROTIC SYNDROME, TYPE 2, SUSCEPTIBILITY TO (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0087

MetaSVM

Uncertain

0.010

MutationAssessor

Benign

1.7

PhyloP100

2.5

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.58

Sift

Benign

0.21

Sift4G

Benign

0.18

Varity_R

0.42

gMVP

0.66

Mutation Taster

=59/41

disease causing (ClinVar)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over