rs559836164

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_014625.4(NPHS2):c.124G>A(p.Gly42Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000596 in 1,516,052 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G42A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0034 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 2 hom. )

Consequence

NPHS2
NM_014625.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: -0.311

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 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=0.006454259).

BP6

Variant 1-179575741-C-T is Benign according to our data. Variant chr1-179575741-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 550771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00342 (521/152156) while in subpopulation AFR AF = 0.0118 (492/41556). AF 95% confidence interval is 0.011. There are 4 homozygotes in GnomAd4. There are 220 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4 link	c.124G>A	p.Gly42Arg	missense_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.124G>A	p.Gly42Arg	missense_variant	Exon 1 of 8	1	NM_014625.4	ENSP00000356587.4		Q9NP85-1
NPHS2	ENST00000367616.4 link	c.124G>A	p.Gly42Arg	missense_variant	Exon 1 of 7	1		ENSP00000356588.4		Q9NP85-2

Frequencies

GnomAD3 genomes

AF:

0.00343

AC:

521

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000794

AC:

AN:

113346

AF XY:

0.000633

show subpopulations

Gnomad AFR exome

AF:

0.0175

Gnomad AMR exome

AF:

0.00115

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000582

GnomAD4 exome

AF:

0.000280

AC:

382

AN:

1363896

Hom.:

Cov.:

AF XY:

0.000254

AC XY:

171

AN XY:

673002

show subpopulations

Gnomad4 AFR exome

AF:

0.0101

AC:

294

AN:

29058

Gnomad4 AMR exome

AF:

0.000966

AC:

AN:

32084

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

24026

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

33554

Gnomad4 SAS exome

AF:

0.0000919

AC:

AN:

76168

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

37176

Gnomad4 NFE exome

AF:

0.00000748

AC:

AN:

1069852

Gnomad4 Remaining exome

AF:

0.000723

AC:

AN:

56706

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00342

AC:

521

AN:

152156

Hom.:

Cov.:

AF XY:

0.00296

AC XY:

220

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0118

AC:

0.0118394

AN:

0.0118394

Gnomad4 AMR

AF:

0.00150

AC:

0.00150346

AN:

0.00150346

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000294

AC:

0.0000294308

AN:

0.0000294308

Gnomad4 OTH

AF:

0.00190

AC:

0.00189753

AN:

0.00189753

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

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:

0.000953

Hom.:

Bravo

AF:

0.00385

ExAC

AF:

0.000584

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephrotic syndrome, type 2

Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 17, 2017

Counsyl

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Steroid-resistant nephrotic syndrome

Uncertain:1

Apr 03, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

1.3

DANN

Benign

0.87

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.45

T;T

MetaRNN

Benign

0.0065

T;T

MetaSVM

Pathogenic

1.3

MutationAssessor

Benign

1.0

L;L

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.12

N;N

REVEL

Uncertain

0.56

Sift

Benign

0.049

D;D

Sift4G

Benign

0.36

T;T

Polyphen

0.0

B;B

Vest4

0.65

MutPred

0.72

Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);

MVP

0.83

MPC

0.31

ClinPred

0.0044

GERP RS

0.75

Varity_R

0.053

gMVP

0.22

Mutation Taster

=97/3

polymorphism

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over