1-179575778-G-C

Position:

• chr1-179575778-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The ENST00000367615.9(NPHS2):​c.87C>G​(p.Ala29=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 1,497,754 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A29A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0043 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0057 (35 hom.)
• Consequence: NPHS2 ENST00000367615.9 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -1.24

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-179575778-G-C is Benign according to our data. Variant chr1-179575778-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260431.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=4}.
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.87C>G	p.Ala29=	synonymous_variant	1/8	ENST00000367615.9	NP_055440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9	c.87C>G	p.Ala29=	synonymous_variant	1/8	1	NM_014625.4	ENSP00000356587	P1
NPHS2	ENST00000367616.4	c.87C>G	p.Ala29=	synonymous_variant	1/7	1		ENSP00000356588

Frequencies

GnomAD3 genomes AF: 0.00427 AC: 649 AN: 152076 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00972

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00563

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00480 AC: 486 AN: 101244 Hom.: 1 AF XY: 0.00522 AC XY: 298 AN XY: 57116

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00331

Gnomad ASJ exome AF: 0.00192

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00678

Gnomad FIN exome AF: 0.00793

Gnomad NFE exome AF: 0.00544

Gnomad OTH exome AF: 0.00369

GnomAD4 exome AF: 0.00572 AC: 7694 AN: 1345570 Hom.: 35 Cov.: 37 AF XY: 0.00583 AC XY: 3872 AN XY: 664110

Gnomad4 AFR exome AF: 0.000543

Gnomad4 AMR exome AF: 0.00368

Gnomad4 ASJ exome AF: 0.00208

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00783

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.00592

Gnomad4 OTH exome AF: 0.00463

GnomAD4 genome AF: 0.00426 AC: 649 AN: 152184 Hom.: 0 Cov.: 34 AF XY: 0.00468 AC XY: 348 AN XY: 74382

Gnomad4 AFR AF: 0.000939

Gnomad4 AMR AF: 0.00569

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00972

Gnomad4 NFE AF: 0.00563

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00251 Hom.: 0

Bravo AF: 0.00350

Asia WGS AF: 0.00116 AC: 4 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	NPHS2: BP4, BP7 -

Nephrotic syndrome, type 2 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 04, 2016

- -

Steroid-resistant nephrotic syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 06, 2020

- -

NPHS2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 28, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Focal segmental glomerulosclerosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.59

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

Other links and lift over

dbSNP: rs12123397; hg19: chr1-179544913;