rs74315344

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_014625.4(NPHS2):c.59C>T(p.Pro20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,477,634 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0041 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0016 ( 7 hom. )

Consequence

NPHS2
NM_014625.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:13

Conservation

PhyloP100: 1.66

Publications

27 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: Illumina, Labcorp Genetics (formerly Invitae), G2P, Myriad Women's Health, Ambry Genetics
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.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

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 familial idiopathic steroid-resistant nephrotic syndrome, nephrotic syndrome, type 2.

BP4

Computational evidence support a benign effect (MetaRNN=0.059987664).

BP6

Variant 1-179575806-G-A is Benign according to our data. Variant chr1-179575806-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5365.

BS2

High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	NM_014625.4	MANE Select	c.59C>T	p.Pro20Leu	missense	Exon 1 of 8	NP_055440.1	Q9NP85-1
	NPHS2	NM_001297575.2		c.59C>T	p.Pro20Leu	missense	Exon 1 of 7	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.59C>T	p.Pro20Leu	missense	Exon 1 of 8	ENSP00000356587.4	Q9NP85-1
NPHS2	ENST00000367616.4	TSL:1	c.59C>T	p.Pro20Leu	missense	Exon 1 of 7	ENSP00000356588.4	Q9NP85-2
NPHS2	ENST00000902256.1		c.59C>T	p.Pro20Leu	missense	Exon 1 of 6	ENSP00000572315.1

Frequencies

GnomAD3 genomes

AF:

0.00410

AC:

623

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00934

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000388

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.00206

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00279

AC:

248

AN:

89040

AF XY:

0.00279

show subpopulations

Gnomad AFR exome

AF:

0.0136

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.000235

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000351

Gnomad NFE exome

AF:

0.00198

Gnomad OTH exome

AF:

0.00344

GnomAD4 exome

AF:

0.00157

AC:

2084

AN:

1325434

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

1074

AN XY:

653660

show subpopulations

African (AFR)

AF:

0.0107

AC:

287

AN:

26724

American (AMR)

AF:

0.00215

AC:

AN:

23246

Ashkenazi Jewish (ASJ)

AF:

0.000285

AC:

AN:

21052

East Asian (EAS)

AF:

0.00

AC:

AN:

32482

South Asian (SAS)

AF:

0.00468

AC:

317

AN:

67732

European-Finnish (FIN)

AF:

0.000837

AC:

AN:

39420

Middle Eastern (MID)

AF:

0.00990

AC:

AN:

5250

European-Non Finnish (NFE)

AF:

0.00113

AC:

1194

AN:

1054896

Other (OTH)

AF:

0.00265

AC:

145

AN:

54632

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

122

244

367

489

611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00409

AC:

623

AN:

152200

Hom.:

Cov.:

AF XY:

0.00414

AC XY:

308

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00931

AC:

387

AN:

41552

American (AMR)

AF:

0.00222

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000390

AC:

AN:

5134

South Asian (SAS)

AF:

0.00456

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00206

AC:

140

AN:

67988

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00233

Hom.:

Bravo

AF:

0.00437

Asia WGS

AF:

0.00231

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nephrotic syndrome, type 2 (5)

not provided (5)

not specified (2)

Finnish congenital nephrotic syndrome (1)

Focal segmental glomerulosclerosis (1)

NPHS2-related disorder (1)

Steroid-resistant nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.63

MetaRNN

Benign

0.060

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.6

PhyloP100

1.7

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.61

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.019

PromoterAI

0.0022

Neutral

(source)

Varity_R

0.072

gMVP

0.33

Mutation Taster

=97/3

polymorphism

(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

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over