chr1-179557040-G-A

Position:

• chr1-179557040-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BA1

The NM_014625.4(NPHS2):​c.725C>T​(p.Ala242Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,613,414 control chromosomes in the GnomAD database, including 209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.020 (110 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (99 hom.)
• Consequence: NPHS2 NM_014625.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.50

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 -11 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 259) in uniprot entity PODO_HUMAN there are 94 pathogenic changes around while only 1 benign (99%) in NM_014625.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.005230814).
• BP6: Variant 1-179557040-G-A is Benign according to our data. Variant chr1-179557040-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260429.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.725C>T	p.Ala242Val	missense_variant	5/8	ENST00000367615.9	NP_055440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9	c.725C>T	p.Ala242Val	missense_variant	5/8	1	NM_014625.4	ENSP00000356587	P1
NPHS2	ENST00000367616.4	c.535-2509C>T		intron_variant		1		ENSP00000356588

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3109 AN: 152196 Hom.: 109 Cov.: 32

Gnomad AFR AF: 0.0711

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00536 AC: 1342 AN: 250452 Hom.: 48 AF XY: 0.00392 AC XY: 531 AN XY: 135364

Gnomad AFR exome AF: 0.0731

Gnomad AMR exome AF: 0.00354

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00199 AC: 2906 AN: 1461100 Hom.: 99 Cov.: 31 AF XY: 0.00169 AC XY: 1225 AN XY: 726880

Gnomad4 AFR exome AF: 0.0718

Gnomad4 AMR exome AF: 0.00392

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.00429

GnomAD4 genome AF: 0.0204 AC: 3110 AN: 152314 Hom.: 110 Cov.: 32 AF XY: 0.0201 AC XY: 1494 AN XY: 74474

Gnomad4 AFR AF: 0.0709

Gnomad4 AMR AF: 0.00791

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00418 Hom.: 26

Bravo AF: 0.0241

ESP6500AA AF: 0.0710 AC: 313

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00650 AC: 789

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2020	This variant is associated with the following publications: (PMID: 32691731, 30450462, 26211502, 12707396, 20981092) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Nephrotic syndrome, type 2 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 02, 2018	Variant summary: NPHS2 c.725C>T (p.Ala242Val) results in a non-conservative amino acid change located in the Band 7 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0069 in 276216 control chromosomes, predominantly within the African subpopulation at a frequency of 0.073 in the gnomAD database, including 67 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 41-fold above the estimated maximal expected allele frequency for a pathogenic variant in NPHS2 causing Nephrotic Syndrome, Type 2 phenotype (0.0018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Steroid-resistant nephrotic syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0052	T
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.036	D
Polyphen		0.99	D
Vest4		0.49
MVP		0.89
MPC		0.88
ClinPred		0.033	T
GERP RS		5.9
Varity_R		0.59
gMVP		0.68

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: rs61747727; hg19: chr1-179526175;