1-179551371-G-A

Position:

chr1-179551371-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014625.4(NPHS2):c.954C>T(p.Ala318=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.618 in 1,613,796 control chromosomes in the GnomAD database, including 308,950 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 28814 hom., cov: 31)

Exomes 𝑓: 0.62 ( 280136 hom. )

Consequence

NPHS2
NM_014625.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.562

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:

AXDND1 (HGNC:26564): (axonemal dynein light chain domain containing 1)

AXDND1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 1-179551371-G-A is Benign according to our data. Variant chr1-179551371-G-A is described in ClinVar as [Benign]. Clinvar id is 260432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179551371-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.562 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS2	NM_014625.4 linkuse as main transcript	c.954C>T	p.Ala318=	synonymous_variant	8/8	ENST00000367615.9	NP_055440.1
AXDND1	NM_144696.6 linkuse as main transcript	c.3032-3141G>A		intron_variant		ENST00000367618.8	NP_653297.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9 linkuse as main transcript	c.954C>T	p.Ala318=	synonymous_variant	8/8	1	NM_014625.4	ENSP00000356587	P1	Q9NP85-1
AXDND1	ENST00000367618.8 linkuse as main transcript	c.3032-3141G>A		intron_variant		1	NM_144696.6	ENSP00000356590	P2	Q5T1B0-1

Frequencies

GnomAD3 genomes

AF:

0.614

AC:

93257

AN:

151874

Hom.:

28786

Cov.:

show subpopulations

Gnomad AFR

AF:

0.604

Gnomad AMI

AF:

0.646

Gnomad AMR

AF:

0.638

Gnomad ASJ

AF:

0.640

Gnomad EAS

AF:

0.468

Gnomad SAS

AF:

0.591

Gnomad FIN

AF:

0.619

Gnomad MID

AF:

0.604

Gnomad NFE

AF:

0.625

Gnomad OTH

AF:

0.608

GnomAD3 exomes

AF:

0.619

AC:

155359

AN:

250964

Hom.:

48514

AF XY:

0.618

AC XY:

83835

AN XY:

135584

show subpopulations

Gnomad AFR exome

AF:

0.600

Gnomad AMR exome

AF:

0.665

Gnomad ASJ exome

AF:

0.659

Gnomad EAS exome

AF:

0.473

Gnomad SAS exome

AF:

0.604

Gnomad FIN exome

AF:

0.622

Gnomad NFE exome

AF:

0.631

Gnomad OTH exome

AF:

0.624

GnomAD4 exome

AF:

0.618

AC:

903486

AN:

1461802

Hom.:

280136

Cov.:

AF XY:

0.618

AC XY:

449545

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.600

Gnomad4 AMR exome

AF:

0.663

Gnomad4 ASJ exome

AF:

0.659

Gnomad4 EAS exome

AF:

0.507

Gnomad4 SAS exome

AF:

0.602

Gnomad4 FIN exome

AF:

0.622

Gnomad4 NFE exome

AF:

0.621

Gnomad4 OTH exome

AF:

0.618

GnomAD4 genome

AF:

0.614

AC:

93340

AN:

151994

Hom.:

28814

Cov.:

AF XY:

0.613

AC XY:

45530

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.604

Gnomad4 AMR

AF:

0.639

Gnomad4 ASJ

AF:

0.640

Gnomad4 EAS

AF:

0.468

Gnomad4 SAS

AF:

0.591

Gnomad4 FIN

AF:

0.619

Gnomad4 NFE

AF:

0.625

Gnomad4 OTH

AF:

0.608

Alfa

AF:

0.625

Hom.:

59010

Bravo

AF:

0.616

Asia WGS

AF:

0.565

AC:

1966

AN:

3478

EpiCase

AF:

0.627

EpiControl

AF:

0.628

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 86% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 80. Only high quality variants are reported. -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 05, 2016	Variant summary: The NPHS2 c.954C>T (p.Ala318Ala) variant involves the alteration of a non-conserved nucleotide resulting in a synonymous change. One in silico tool (MutationTaster) predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing, howevere these predictions are yet to be confirmed by the functional studies. This variant was found in 75096/121278 control chromosomes (including 23360 homozygotes) at a frequency of 0.6192055, which is approximately 350 times the estimated maximal expected allele frequency of a pathogenic NPHS2 variant (0.0017678), suggesting this variant is a common benign polymorphism. The variant of interest has also been cited as a polymorphism in published reports (Rachmadi_2015). Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nephrotic syndrome, type 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -

Steroid-resistant nephrotic syndrome

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.17

DANN

Benign

0.63

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