rs3738423

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014625.4(NPHS2):c.288C>T(p.Ser96Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0842 in 1,612,474 control chromosomes in the GnomAD database, including 6,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.084 ( 615 hom., cov: 32)

Exomes 𝑓: 0.084 ( 5692 hom. )

Consequence

NPHS2
NM_014625.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.42

Publications

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

NPHS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 1-179564780-G-A is Benign according to our data. Variant chr1-179564780-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.42 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4 link	c.288C>T	p.Ser96Ser	synonymous_variant	Exon 2 of 8	ENST00000367615.9	NP_055440.1	Q9NP85-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9 link	c.288C>T	p.Ser96Ser	synonymous_variant	Exon 2 of 8	1	NM_014625.4	ENSP00000356587.4		Q9NP85-1
NPHS2	ENST00000367616.4 link	c.288C>T	p.Ser96Ser	synonymous_variant	Exon 2 of 7	1		ENSP00000356588.4		Q9NP85-2

Frequencies

GnomAD3 genomes

AF:

0.0841

AC:

12797

AN:

152076

Hom.:

615

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0882

Gnomad AMI

AF:

0.112

Gnomad AMR

AF:

0.0596

Gnomad ASJ

AF:

0.0747

Gnomad EAS

AF:

0.0889

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.131

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0852

Gnomad OTH

AF:

0.0784

GnomAD2 exomes

AF:

0.0734

AC:

18446

AN:

251188

AF XY:

0.0706

show subpopulations

Gnomad AFR exome

AF:

0.0896

Gnomad AMR exome

AF:

0.0355

Gnomad ASJ exome

AF:

0.0634

Gnomad EAS exome

AF:

0.0939

Gnomad FIN exome

AF:

0.131

Gnomad NFE exome

AF:

0.0851

Gnomad OTH exome

AF:

0.0760

GnomAD4 exome

AF:

0.0842

AC:

122921

AN:

1460280

Hom.:

5692

Cov.:

AF XY:

0.0815

AC XY:

59206

AN XY:

726504

show subpopulations

African (AFR)

AF:

0.0846

AC:

2830

AN:

33458

American (AMR)

AF:

0.0375

AC:

1678

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0644

AC:

1682

AN:

26126

East Asian (EAS)

AF:

0.0675

AC:

2679

AN:

39686

South Asian (SAS)

AF:

0.0138

AC:

1186

AN:

86240

European-Finnish (FIN)

AF:

0.131

AC:

6990

AN:

53408

Middle Eastern (MID)

AF:

0.0135

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0908

AC:

100818

AN:

1110562

Other (OTH)

AF:

0.0825

AC:

4980

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

5391

10782

16173

21564

26955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3772

7544

11316

15088

18860

<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:

0.0841

AC:

12803

AN:

152194

Hom.:

615

Cov.:

AF XY:

0.0832

AC XY:

6191

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0881

AC:

3657

AN:

41516

American (AMR)

AF:

0.0595

AC:

910

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0747

AC:

259

AN:

3468

East Asian (EAS)

AF:

0.0891

AC:

462

AN:

5186

South Asian (SAS)

AF:

0.0137

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.131

AC:

1381

AN:

10576

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0852

AC:

5794

AN:

68014

Other (OTH)

AF:

0.0781

AC:

165

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

586

1172

1758

2344

2930

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<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:

0.0799

Hom.:

497

Bravo

AF:

0.0798

Asia WGS

AF:

0.0380

AC:

133

AN:

3478

EpiCase

AF:

0.0764

EpiControl

AF:

0.0756

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephrotic syndrome, type 2

Benign:3

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 29, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Steroid-resistant nephrotic syndrome

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

3.3

(source)

DANN

Benign

0.22

PhyloP100

-2.4

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over