1-179552596-T-C

Variant names:

Variant summary

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

The NM_014625.4(NPHS2):c.873+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 1,611,690 control chromosomes in the GnomAD database, including 1,524 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 97 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1427 hom. )

Consequence

NPHS2
NM_014625.4 splice_region, intron

Scores

Splicing: ADA: 0.0003180

Clinical Significance

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

Conservation

PhyloP100: -0.316

Variant links:

Genes affected

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

AXDND1 links:

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 (BayesDel_noAF=-0.76).

BP6

Variant 1-179552596-T-C is Benign according to our data. Variant chr1-179552596-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 260430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179552596-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0297 (4521/152122) while in subpopulation NFE AF= 0.0478 (3252/67980). AF 95% confidence interval is 0.0465. There are 97 homozygotes in gnomad4. There are 2063 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 97 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXDND1	NM_144696.6 link	c.3032-1916T>C		intron_variant	Intron 25 of 25	ENST00000367618.8	NP_653297.3	Q5T1B0-1
NPHS2	NM_014625.4 link	c.873+7A>G		splice_region_variant, intron_variant	Intron 7 of 7	ENST00000367615.9	NP_055440.1	Q9NP85-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXDND1	ENST00000367618.8 link	c.3032-1916T>C		intron_variant	Intron 25 of 25	1	NM_144696.6	ENSP00000356590.3		Q5T1B0-1
NPHS2	ENST00000367615.9 link	c.873+7A>G		splice_region_variant, intron_variant	Intron 7 of 7	1	NM_014625.4	ENSP00000356587.4		Q9NP85-1

Frequencies

GnomAD3 genomes

AF:

0.0297

AC:

4520

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00725

Gnomad AMI

AF:

0.0462

Gnomad AMR

AF:

0.0343

Gnomad ASJ

AF:

0.0300

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00872

Gnomad FIN

AF:

0.0133

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0478

Gnomad OTH

AF:

0.0454

GnomAD3 exomes

AF:

0.0305

AC:

7600

AN:

249328

Hom.:

204

AF XY:

0.0314

AC XY:

4234

AN XY:

134666

show subpopulations

Gnomad AFR exome

AF:

0.00822

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.0283

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0103

Gnomad FIN exome

AF:

0.0162

Gnomad NFE exome

AF:

0.0488

Gnomad OTH exome

AF:

0.0356

GnomAD4 exome

AF:

0.0403

AC:

58816

AN:

1459568

Hom.:

1427

Cov.:

AF XY:

0.0397

AC XY:

28818

AN XY:

726082

show subpopulations

Gnomad4 AFR exome

AF:

0.00813

Gnomad4 AMR exome

AF:

0.0251

Gnomad4 ASJ exome

AF:

0.0293

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0108

Gnomad4 FIN exome

AF:

0.0164

Gnomad4 NFE exome

AF:

0.0470

Gnomad4 OTH exome

AF:

0.0391

GnomAD4 genome

AF:

0.0297

AC:

4521

AN:

152122

Hom.:

Cov.:

AF XY:

0.0277

AC XY:

2063

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00728

Gnomad4 AMR

AF:

0.0343

Gnomad4 ASJ

AF:

0.0300

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00872

Gnomad4 FIN

AF:

0.0133

Gnomad4 NFE

AF:

0.0478

Gnomad4 OTH

AF:

0.0449

Alfa

AF:

0.0378

Hom.:

Bravo

AF:

0.0307

Asia WGS

AF:

0.00838

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephrotic syndrome, type 2

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Steroid-resistant nephrotic syndrome

Benign:1

Nov 25, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis

Benign:1

Sep 02, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.78

DANN

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00032

dbscSNV1_RF

Benign

0.064

SpliceAI score (max)

0.060

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