chr1-179559745-CA-C

Variant names:

• chr1-179559745-CA-C
• rs528833893
• NM_014625.4:c.467delT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_014625.4(NPHS2):​c.467delT​(p.Leu156CysfsTer25) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000274 in 1,423,464 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPHS2 NM_014625.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.96
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, G2P
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-179559745-CA-C is Pathogenic according to our data. Variant chr1-179559745-CA-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4086126.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014625.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	NM_014625.4	MANE Select	c.467delT	p.Leu156CysfsTer25	frameshift	Exon 4 of 8	NP_055440.1
	NPHS2	NM_001297575.2		c.467delT	p.Leu156CysfsTer29	frameshift	Exon 4 of 7	NP_001284504.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	ENST00000367615.9	TSL:1 MANE Select	c.467delT	p.Leu156CysfsTer25	frameshift	Exon 4 of 8	ENSP00000356587.4
	NPHS2	ENST00000367616.4	TSL:1	c.467delT	p.Leu156CysfsTer29	frameshift	Exon 4 of 7	ENSP00000356588.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 150808 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000210 AC: 43 AN: 204742 AF XY: 0.000266

Gnomad AFR exome AF: 0.0000818

Gnomad AMR exome AF: 0.0000965

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000524

Gnomad NFE exome AF: 0.000407

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 39 AN: 1423464 Hom.: 0 Cov.: 30 AF XY: 0.0000354 AC XY: 25 AN XY: 705630

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32632

American (AMR) AF: 0.0000474 AC: 2 AN: 42168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25324

East Asian (EAS) AF: 0.00 AC: 0 AN: 38542

South Asian (SAS) AF: 0.0000729 AC: 6 AN: 82360

European-Finnish (FIN) AF: 0.0000389 AC: 2 AN: 51458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.0000248 AC: 27 AN: 1086564

Other (OTH) AF: 0.0000340 AC: 2 AN: 58738

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 150808 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73508

African (AFR) AF: 0.00 AC: 0 AN: 40986

American (AMR) AF: 0.00 AC: 0 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67710

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephrotic syndrome, type 2 Pathogenic:1

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=3/197	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs528833893; hg19: chr1-179528880; COSMIC: COSV62634776;