1-179559690-G-A

Variant names:

• chr1-179559690-G-A
• rs1472510122
• NM_014625.4:c.523C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_014625.4(NPHS2):​c.523C>T​(p.Pro175Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000698 in 1,433,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P175T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NPHS2 NM_014625.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.73
• Publications: 2 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 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_014625.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.68612 (below the threshold of 3.09). Trascript score misZ: 0.038296 (below the threshold of 3.09). GenCC associations: The gene is linked to nephrotic syndrome, type 2, familial idiopathic steroid-resistant nephrotic syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

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.523C>T	p.Pro175Ser	missense	Exon 4 of 8	NP_055440.1	Q9NP85-1
	NPHS2	NM_001297575.2		c.523C>T	p.Pro175Ser	missense	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.523C>T	p.Pro175Ser	missense	Exon 4 of 8	ENSP00000356587.4	Q9NP85-1
	NPHS2	ENST00000367616.4	TSL:1	c.523C>T	p.Pro175Ser	missense	Exon 4 of 7	ENSP00000356588.4	Q9NP85-2
	NPHS2	ENST00000902256.1		c.346C>T	p.Pro116Ser	missense	Exon 2 of 6	ENSP00000572315.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1433002 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 710282

African (AFR) AF: 0.00 AC: 0 AN: 32754

American (AMR) AF: 0.00 AC: 0 AN: 42604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25522

East Asian (EAS) AF: 0.00 AC: 0 AN: 38778

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094104

Other (OTH) AF: 0.00 AC: 0 AN: 59170

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Nephrotic syndrome, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.97	D
Vest4		0.85
MutPred		0.56		Loss of stability (P = 0.1934)
MVP		0.97
MPC		0.92
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.86
gMVP		0.86
Mutation Taster		=25/75	disease causing

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: rs1472510122; hg19: chr1-179528825;