rs786204583

Variant names:

• chr1-179559711-G-A
• rs786204583
• NM_014625.4:c.502C>T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_014625.4(NPHS2):​c.502C>T​(p.Arg168Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,439,948 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003523922: Experimental studies have shown that this missense change affects NPHS2 function (PMID:14675423).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R168H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NPHS2 NM_014625.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.71
• Publications: 9 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: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003523922: Experimental studies have shown that this missense change affects NPHS2 function (PMID: 14675423).
• PM1: In a hotspot region, there are 4 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-179559710-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 1-179559711-G-A is Pathogenic according to our data. Variant chr1-179559711-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	NM_014625.4	MANE Select	c.502C>T	p.Arg168Cys	missense	Exon 4 of 8	NP_055440.1	Q9NP85-1
	NPHS2	NM_001297575.2		c.502C>T	p.Arg168Cys	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.502C>T	p.Arg168Cys	missense	Exon 4 of 8	ENSP00000356587.4	Q9NP85-1
	NPHS2	ENST00000367616.4	TSL:1	c.502C>T	p.Arg168Cys	missense	Exon 4 of 7	ENSP00000356588.4	Q9NP85-2
	NPHS2	ENST00000902256.1		c.325C>T	p.Arg109Cys	missense	Exon 2 of 6	ENSP00000572315.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 221518 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1439948 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 714140

African (AFR) AF: 0.0000304 AC: 1 AN: 32934

American (AMR) AF: 0.00 AC: 0 AN: 43080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25584

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39054

South Asian (SAS) AF: 0.00 AC: 0 AN: 83130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098834

Other (OTH) AF: 0.00 AC: 0 AN: 59438

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Nephrotic syndrome, type 2 (5)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		5.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.95		Gain of catalytic residue at L169 (P = 0.0211)
MVP		0.93
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.92
gMVP		0.94
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs786204583; hg19: chr1-179528846; COSMIC: COSV62635309; COSMIC: COSV62635309;