rs12406197

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014625.4(NPHS2):c.-51G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 1,358,458 control chromosomes in the GnomAD database, including 47,137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4506 hom., cov: 34)

Exomes 𝑓: 0.26 ( 42631 hom. )

Consequence

NPHS2
NM_014625.4 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:13

Conservation

PhyloP100: -1.14

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 1-179575915-C-A is Benign according to our data. Variant chr1-179575915-C-A is described in ClinVar as [Benign]. Clinvar id is 225144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4 link	c.-51G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	ENST00000367615.9	NP_055440.1	Q9NP85-1
NPHS2	NM_014625.4 link	c.-51G>T		5_prime_UTR_variant	Exon 1 of 8	ENST00000367615.9	NP_055440.1	Q9NP85-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPHS2	ENST00000367615.9 link	c.-51G>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	1	NM_014625.4	ENSP00000356587.4	Q9NP85-1
NPHS2	ENST00000367616.4 link	c.-51G>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	1		ENSP00000356588.4	Q9NP85-2
NPHS2	ENST00000367615.9 link	c.-51G>T	5_prime_UTR_variant	Exon 1 of 8	1	NM_014625.4	ENSP00000356587.4	Q9NP85-1
NPHS2	ENST00000367616.4 link	c.-51G>T	5_prime_UTR_variant	Exon 1 of 7	1		ENSP00000356588.4	Q9NP85-2

Frequencies

GnomAD3 genomes

AF:

0.237

AC:

35998

AN:

152074

Hom.:

4502

Cov.:

show subpopulations

Gnomad AFR

AF:

0.160

Gnomad AMI

AF:

0.202

Gnomad AMR

AF:

0.268

Gnomad ASJ

AF:

0.340

Gnomad EAS

AF:

0.113

Gnomad SAS

AF:

0.208

Gnomad FIN

AF:

0.306

Gnomad MID

AF:

0.210

Gnomad NFE

AF:

0.273

Gnomad OTH

AF:

0.232

GnomAD2 exomes

AF:

0.255

AC:

5501

AN:

21614

AF XY:

0.254

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.345

Gnomad ASJ exome

AF:

0.374

Gnomad EAS exome

AF:

0.0981

Gnomad FIN exome

AF:

0.325

Gnomad NFE exome

AF:

0.277

Gnomad OTH exome

AF:

0.299

GnomAD4 exome

AF:

0.263

AC:

316772

AN:

1206276

Hom.:

42631

Cov.:

AF XY:

0.263

AC XY:

153097

AN XY:

583210

show subpopulations

African (AFR)

AF:

0.145

AC:

3489

AN:

24016

American (AMR)

AF:

0.299

AC:

3478

AN:

11628

Ashkenazi Jewish (ASJ)

AF:

0.340

AC:

5573

AN:

16378

East Asian (EAS)

AF:

0.129

AC:

3813

AN:

29474

South Asian (SAS)

AF:

0.221

AC:

10381

AN:

46876

European-Finnish (FIN)

AF:

0.308

AC:

9086

AN:

29498

Middle Eastern (MID)

AF:

0.238

AC:

838

AN:

3518

European-Non Finnish (NFE)

AF:

0.269

AC:

267659

AN:

995234

Other (OTH)

AF:

0.251

AC:

12455

AN:

49654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

12226

24452

36679

48905

61131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9622

19244

28866

38488

48110

<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:

0.237

AC:

36016

AN:

152182

Hom.:

4506

Cov.:

AF XY:

0.238

AC XY:

17719

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.160

AC:

6636

AN:

41562

American (AMR)

AF:

0.269

AC:

4122

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.340

AC:

1181

AN:

3472

East Asian (EAS)

AF:

0.112

AC:

580

AN:

5156

South Asian (SAS)

AF:

0.209

AC:

1008

AN:

4830

European-Finnish (FIN)

AF:

0.306

AC:

3242

AN:

10590

Middle Eastern (MID)

AF:

0.209

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.273

AC:

18518

AN:

67948

Other (OTH)

AF:

0.229

AC:

484

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1462

2923

4385

5846

7308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

374

748

1122

1496

1870

<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:

0.259

Hom.:

636

Bravo

AF:

0.232

Asia WGS

AF:

0.161

AC:

558

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 41% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 38. Only high quality variants are reported. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2022

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nephrotic syndrome, type 2

Pathogenic:1Benign:2

Jan 01, 2016

Human Genetics Disease in Children – Taif University, Taif University

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 20, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16900088, 30793612) -

NPHS2-related disorder

Benign:1

Feb 23, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Focal segmental glomerulosclerosis

Benign:1

Sep 27, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

4.3

(source)

DANN

Benign

0.84

PhyloP100

-1.1

PromoterAI

0.022

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(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

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