rs139111416

chr1-179561293-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_014625.4(NPHS2):c.447C>T(p.Gly149=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00338 in 1,611,830 control chromosomes in the GnomAD database, including 13 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 0.0027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (12 hom.)
• Consequence: NPHS2 NM_014625.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.472

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-179561293-G-A is Benign according to our data. Variant chr1-179561293-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 586185.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=2}.
• BP7: Synonymous conserved (PhyloP=-0.472 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS2	NM_014625.4	c.447C>T	p.Gly149=	synonymous_variant	3/8	ENST00000367615.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS2	ENST00000367615.9	c.447C>T	p.Gly149=	synonymous_variant	3/8	1	NM_014625.4	P1
NPHS2	ENST00000367616.4	c.447C>T	p.Gly149=	synonymous_variant	3/7	1

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 416 AN: 152084 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00491

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00454

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00251 AC: 630 AN: 251354 Hom.: 3 AF XY: 0.00249 AC XY: 338 AN XY: 135850

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00522

Gnomad NFE exome AF: 0.00398

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00345 AC: 5040 AN: 1459628 Hom.: 12 Cov.: 29 AF XY: 0.00335 AC XY: 2432 AN XY: 726324

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00556

Gnomad4 NFE exome AF: 0.00409

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152202 Hom.: 1 Cov.: 33 AF XY: 0.00247 AC XY: 184 AN XY: 74414

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00491

Gnomad4 NFE AF: 0.00454

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00328 Hom.: 1

Bravo AF: 0.00231

EpiCase AF: 0.00382

EpiControl AF: 0.00350

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	NPHS2: BP4, BP7, BS2 -

Nephrotic syndrome, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	9.5
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs139111416; hg19: chr1-179530428;