chr1-179575763-T-C

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.102A>G(p.Gly34Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.983 in 1,496,666 control chromosomes in the GnomAD database, including 723,969 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.95 ( 68595 hom., cov: 32)

Exomes 𝑓: 0.99 ( 655374 hom. )

Consequence

NPHS2
NM_014625.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.412

Publications

18 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=-0.98).

BP6

Variant 1-179575763-T-C is Benign according to our data. Variant chr1-179575763-T-C is described in ClinVar as Benign. ClinVar VariationId is 260424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.412 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4 link	c.102A>G	p.Gly34Gly	synonymous_variant	Exon 1 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.102A>G	p.Gly34Gly	synonymous_variant	Exon 1 of 8	1	NM_014625.4	ENSP00000356587.4		Q9NP85-1
NPHS2	ENST00000367616.4 link	c.102A>G	p.Gly34Gly	synonymous_variant	Exon 1 of 7	1		ENSP00000356588.4		Q9NP85-2

Frequencies

GnomAD3 genomes

AF:

0.947

AC:

143975

AN:

151962

Hom.:

68551

Cov.:

show subpopulations

Gnomad AFR

AF:

0.844

Gnomad AMI

AF:

0.962

Gnomad AMR

AF:

0.975

Gnomad ASJ

AF:

0.988

Gnomad EAS

AF:

0.978

Gnomad SAS

AF:

0.941

Gnomad FIN

AF:

0.994

Gnomad MID

AF:

0.962

Gnomad NFE

AF:

0.993

Gnomad OTH

AF:

0.951

GnomAD2 exomes

AF:

0.977

AC:

96167

AN:

98386

AF XY:

0.976

show subpopulations

Gnomad AFR exome

AF:

0.807

Gnomad AMR exome

AF:

0.986

Gnomad ASJ exome

AF:

0.989

Gnomad EAS exome

AF:

0.975

Gnomad FIN exome

AF:

0.995

Gnomad NFE exome

AF:

0.993

Gnomad OTH exome

AF:

0.980

GnomAD4 exome

AF:

0.987

AC:

1327035

AN:

1344596

Hom.:

655374

Cov.:

AF XY:

0.986

AC XY:

654062

AN XY:

663274

show subpopulations

African (AFR)

AF:

0.838

AC:

23052

AN:

27496

American (AMR)

AF:

0.983

AC:

27848

AN:

28332

Ashkenazi Jewish (ASJ)

AF:

0.987

AC:

22789

AN:

23094

East Asian (EAS)

AF:

0.977

AC:

31547

AN:

32296

South Asian (SAS)

AF:

0.948

AC:

69493

AN:

73330

European-Finnish (FIN)

AF:

0.995

AC:

37937

AN:

38122

Middle Eastern (MID)

AF:

0.961

AC:

4804

AN:

4998

European-Non Finnish (NFE)

AF:

0.994

AC:

1055128

AN:

1061232

Other (OTH)

AF:

0.977

AC:

54437

AN:

55696

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

902

1803

2705

3606

4508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21132

42264

63396

84528

105660

<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:

0.947

AC:

144070

AN:

152070

Hom.:

68595

Cov.:

AF XY:

0.948

AC XY:

70438

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.844

AC:

35035

AN:

41514

American (AMR)

AF:

0.976

AC:

14926

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.988

AC:

3431

AN:

3472

East Asian (EAS)

AF:

0.978

AC:

4987

AN:

5100

South Asian (SAS)

AF:

0.941

AC:

4540

AN:

4826

European-Finnish (FIN)

AF:

0.994

AC:

10521

AN:

10588

Middle Eastern (MID)

AF:

0.962

AC:

281

AN:

292

European-Non Finnish (NFE)

AF:

0.993

AC:

67463

AN:

67954

Other (OTH)

AF:

0.951

AC:

2009

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

351

702

1053

1404

1755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.972

Hom.:

12293

Bravo

AF:

0.942

Asia WGS

AF:

0.942

AC:

3249

AN:

3450

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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 95% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 88. Only high quality variants are reported. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nephrotic syndrome, type 2

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 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. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Steroid-resistant nephrotic syndrome

Benign:1

Nov 16, 2019

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

-0.98

CADD

Benign

0.62

(source)

DANN

Benign

0.35

PhyloP100

-0.41

PromoterAI

-0.12

Neutral

(source)

Mutation Taster

=100/0

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