dbSNP rs559836164: NPHS2:p.Gly42Arg (chr1-179575741-C-T) – ACMG Classification: Benign (-19 pts)

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. 12/21 in silico tools predict 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

Publications

1 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), Myriad Women’s Health, Ambry Genetics, 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 -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 nephrotic syndrome, type 2, familial idiopathic steroid-resistant nephrotic syndrome.

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 Benign/Likely_benign. ClinVar VariationId 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 passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD 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.124G>A	p.Gly42Arg	missense	Exon 1 of 8	NP_055440.1	Q9NP85-1
	NPHS2	NM_001297575.2		c.124G>A	p.Gly42Arg	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.124G>A	p.Gly42Arg	missense	Exon 1 of 8	ENSP00000356587.4	Q9NP85-1
NPHS2	ENST00000367616.4	TSL:1	c.124G>A	p.Gly42Arg	missense	Exon 1 of 7	ENSP00000356588.4	Q9NP85-2
NPHS2	ENST00000902256.1		c.124G>A	p.Gly42Arg	missense	Exon 1 of 6	ENSP00000572315.1

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

African (AFR)

AF:

0.0101

AC:

294

AN:

29058

American (AMR)

AF:

0.000966

AC:

AN:

32084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24026

East Asian (EAS)

AF:

0.00

AC:

AN:

33554

South Asian (SAS)

AF:

0.0000919

AC:

AN:

76168

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37176

Middle Eastern (MID)

AF:

0.000190

AC:

AN:

5272

European-Non Finnish (NFE)

AF:

0.00000748

AC:

AN:

1069852

Other (OTH)

AF:

0.000723

AC:

AN:

56706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.0118

AC:

492

AN:

41556

American (AMR)

AF:

0.00150

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5130

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67956

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nephrotic syndrome, type 2 (2)

not provided (1)

Steroid-resistant nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

1.3

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.17

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0065

MetaSVM

Pathogenic

1.3

MutationAssessor

Benign

1.0

PhyloP100

-0.31

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.12

REVEL

Uncertain

0.56

Sift

Benign

0.049

Sift4G

Benign

0.36

Polyphen

0.0

Vest4

0.65

MutPred

0.72

Gain of MoRF binding (P = 0.013)

MVP

0.83

MPC

0.31

ClinPred

0.0044

GERP RS

0.75

PromoterAI

0.065

Neutral

(source)

Varity_R

0.053

gMVP

0.22

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

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