chr1-179559745-C-CA

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_014625.4(NPHS2):​c.467dupT​(p.Leu156PhefsTer11) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000502 in 1,574,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: NPHS2 NM_014625.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:15 U:2
• 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: Illumina, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Ambry Genetics, G2P
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-179559745-C-CA is Pathogenic according to our data. Variant chr1-179559745-C-CA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 556941.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	NM_014625.4	MANE Select	c.467dupT	p.Leu156PhefsTer11	frameshift	Exon 4 of 8	NP_055440.1	Q9NP85-1
	NPHS2	NM_001297575.2		c.467dupT	p.Leu156PhefsTer11	frameshift	Exon 4 of 7	NP_001284504.1	Q9NP85-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	ENST00000367615.9	TSL:1 MANE Select	c.467dupT	p.Leu156PhefsTer11	frameshift	Exon 4 of 8	ENSP00000356587.4	Q9NP85-1
	NPHS2	ENST00000367616.4	TSL:1	c.467dupT	p.Leu156PhefsTer11	frameshift	Exon 4 of 7	ENSP00000356588.4	Q9NP85-2
	NPHS2	ENST00000902256.1		c.290dupT	p.Leu97PhefsTer11	frameshift	Exon 2 of 6	ENSP00000572315.1

Frequencies

GnomAD3 genomes AF: 0.0000464 AC: 7 AN: 150806 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.000205 AC: 42 AN: 204742 AF XY: 0.000229

Gnomad AFR exome AF: 0.000572

Gnomad AMR exome AF: 0.000161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000190

Gnomad FIN exome AF: 0.000157

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.000189

GnomAD4 exome AF: 0.0000513 AC: 73 AN: 1423766 Hom.: 0 Cov.: 30 AF XY: 0.0000468 AC XY: 33 AN XY: 705762

⚠️ 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: 32628

American (AMR) AF: 0.000142 AC: 6 AN: 42166

Ashkenazi Jewish (ASJ) AF: 0.0000395 AC: 1 AN: 25322

East Asian (EAS) AF: 0.000104 AC: 4 AN: 38546

South Asian (SAS) AF: 0.000109 AC: 9 AN: 82366

European-Finnish (FIN) AF: 0.0000777 AC: 4 AN: 51460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.0000423 AC: 46 AN: 1086846

Other (OTH) AF: 0.0000511 AC: 3 AN: 58756

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000000330846), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000398 AC: 6 AN: 150924 Hom.: 0 Cov.: 32 AF XY: 0.0000543 AC XY: 4 AN XY: 73634

African (AFR) AF: 0.0000487 AC: 2 AN: 41108

American (AMR) AF: 0.00 AC: 0 AN: 15196

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

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5142

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4750

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67702

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000252 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
12	1	-	Nephrotic syndrome, type 2 (13)
1	1	-	not provided (2)
1	-	-	NPHS2-related disorder (1)
1	-	-	Steroid-resistant nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=0/200	disease causing (ClinVar)

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: COSV62634526;