rs201050491

Positions:

chr1-179575683-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014625.4(NPHS2):c.182C>T(p.Ala61Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000937 in 1,596,352 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A61T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0052 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 6 hom. )

Consequence

NPHS2
NM_014625.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.92

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005782157).

BP6

Variant 1-179575683-G-A is Benign according to our data. Variant chr1-179575683-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 447877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179575683-G-A is described in Lovd as [Benign]. Variant chr1-179575683-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00524 (798/152310) while in subpopulation AFR AF= 0.0184 (767/41584). AF 95% confidence interval is 0.0174. There are 6 homozygotes in gnomad4. There are 371 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS2	NM_014625.4 linkuse as main transcript	c.182C>T	p.Ala61Val	missense_variant	1/8	ENST00000367615.9	NP_055440.1	Q9NP85-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9 linkuse as main transcript	c.182C>T	p.Ala61Val	missense_variant	1/8	1	NM_014625.4	ENSP00000356587.4		Q9NP85-1
NPHS2	ENST00000367616.4 linkuse as main transcript	c.182C>T	p.Ala61Val	missense_variant	1/7	1		ENSP00000356588.4		Q9NP85-2

Frequencies

GnomAD3 genomes

AF:

0.00524

AC:

798

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0185

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.0000588

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00115

AC:

246

AN:

213816

Hom.:

AF XY:

0.000824

AC XY:

AN XY:

118934

show subpopulations

Gnomad AFR exome

AF:

0.0183

Gnomad AMR exome

AF:

0.000490

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000104

Gnomad OTH exome

AF:

0.000921

GnomAD4 exome

AF:

0.000483

AC:

698

AN:

1444042

Hom.:

Cov.:

AF XY:

0.000401

AC XY:

288

AN XY:

718286

show subpopulations

Gnomad4 AFR exome

AF:

0.0180

Gnomad4 AMR exome

AF:

0.000686

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000352

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000722

Gnomad4 OTH exome

AF:

0.000918

GnomAD4 genome

AF:

0.00524

AC:

798

AN:

152310

Hom.:

Cov.:

AF XY:

0.00498

AC XY:

371

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0184

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00205

Hom.:

Bravo

AF:

0.00556

ESP6500AA

AF:

0.0151

AC:

ESP6500EA

AF:

0.000246

AC:

ExAC

AF:

0.00124

AC:

145

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 13, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 02, 2016	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Nephrotic syndrome, type 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.74

T;T

MetaRNN

Benign

0.0058

T;T

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

1.6

L;L

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.23

N;N

REVEL

Uncertain

0.34

Sift

Benign

0.19

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.0020

B;P

Vest4

0.19

MVP

0.81

MPC

0.26

ClinPred

0.0067

GERP RS

4.0

Varity_R

0.081

gMVP

0.42

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