1-179575806-G-C

Variant names:

• chr1-179575806-G-C
• rs74315344
• NM_014625.4:c.59C>G
• NPHS2 p.Pro20Arg

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_014625.4(NPHS2):​c.59C>G​(p.Pro20Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P20L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPHS2 NM_014625.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66
• Publications: 0 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), G2P, Myriad Women's Health, Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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 familial idiopathic steroid-resistant nephrotic syndrome, nephrotic syndrome, type 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22814703).

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.59C>G	p.Pro20Arg	missense	Exon 1 of 8	NP_055440.1	Q9NP85-1
	NPHS2	NM_001297575.2		c.59C>G	p.Pro20Arg	missense	Exon 1 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.59C>G	p.Pro20Arg	missense	Exon 1 of 8	ENSP00000356587.4	Q9NP85-1
	NPHS2	ENST00000367616.4	TSL:1	c.59C>G	p.Pro20Arg	missense	Exon 1 of 7	ENSP00000356588.4	Q9NP85-2
	NPHS2	ENST00000902256.1		c.59C>G	p.Pro20Arg	missense	Exon 1 of 6	ENSP00000572315.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1325438 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 653662

African (AFR) AF: 0.00 AC: 0 AN: 26726

American (AMR) AF: 0.00 AC: 0 AN: 23248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21052

East Asian (EAS) AF: 0.00 AC: 0 AN: 32482

South Asian (SAS) AF: 0.00 AC: 0 AN: 67732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5250

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1054896

Other (OTH) AF: 0.00 AC: 0 AN: 54632

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.23	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L
PhyloP100		1.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.053	T
PromoterAI		0.032	Neutral
Varity_R		0.064
gMVP		0.31
Mutation Taster		=95/5	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs74315344;

hg19: chr1-179544941;