1-179561327-C-T

Variant names:

• chr1-179561327-C-T
• rs74315342
• NM_014625.4:c.413G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM5 PP2 PP5_Very_Strong

The NM_014625.4(NPHS2):​c.413G>A​(p.Arg138Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000797 in 1,613,114 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000351504: A review by Bouchireb et al. (2014) indicates that the Arg138 residue is highly conserved among stromatin-like protein family members and the p.Arg138Gln variant protein is retained in the endoplasmic reticulum, rather than targeting normally to the plasma membrane. Bouchireb et al. (2014) also report that a knock-in mouse model homozygous for the equivalent of this variant presents at birth with severe proteinuria and progresses to end-stage kidney disease by five weeks of life.; SCV000699382: Functional studies show that while the variant resulted in a protein that retains the ability to homo-oligomerize, the protein is retained in the ER and fails to recruit nephrin to lipid drafts (Huber_2003).; SCV001164373: Functional studies with mammalian cells provide some evidence that the p.Arg138Gln variant may impact protein function by preventing localization to the plasma membrane from the endoplasmic reticulum and increasing protein degradation (PMID:12649741, 29382718).; SCV000491110: Published functional studies demonstrate a damaging effect with altered protein folding and accumulation in the endoplasmic reticulum instead of the plasma membrane as seen in the wild type (Ohashi et al., 2003; Roselli et al., 2004).; SCV000950662: Experimental studies have shown that this missense change affects NPHS2 function (PMID:12649741, 14570703, 14675423, 29049388).; SCV005414083: PS3; SCV006325376: Experimental studies have demonstrated that this sequence change may impact function of NPHS2 (PMID:12649741, 29382718, 14570703, 14675423, 29049388).; SCV004769508: Functional studies indicate this variant causes aberrant accumulation in the endoplasmic reticulum instead of localization to the plasma membrane (Roselli et al. 2004. PubMed ID: 14675423).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (0 hom.)
• Consequence: NPHS2 NM_014625.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28 U:1
• Conservation: PhyloP100: 6.19
• Publications: 86 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000351504: A review by Bouchireb et al. (2014) indicates that the Arg138 residue is highly conserved among stromatin-like protein family members and the p.Arg138Gln variant protein is retained in the endoplasmic reticulum, rather than targeting normally to the plasma membrane. Bouchireb et al. (2014) also report that a knock-in mouse model homozygous for the equivalent of this variant presents at birth with severe proteinuria and progresses to end-stage kidney disease by five weeks of life.; SCV000699382: Functional studies show that while the variant resulted in a protein that retains the ability to homo-oligomerize, the protein is retained in the ER and fails to recruit nephrin to lipid drafts (Huber_2003).; SCV001164373: Functional studies with mammalian cells provide some evidence that the p.Arg138Gln variant may impact protein function by preventing localization to the plasma membrane from the endoplasmic reticulum and increasing protein degradation (PMID: 12649741, 29382718).; SCV000491110: Published functional studies demonstrate a damaging effect with altered protein folding and accumulation in the endoplasmic reticulum instead of the plasma membrane as seen in the wild type (Ohashi et al., 2003; Roselli et al., 2004).; SCV000950662: Experimental studies have shown that this missense change affects NPHS2 function (PMID: 12649741, 14570703, 14675423, 29049388).; SCV005414083: PS3; SCV006325376: Experimental studies have demonstrated that this sequence change may impact function of NPHS2 (PMID: 12649741, 29382718, 14570703, 14675423, 29049388).; SCV004769508: Functional studies indicate this variant causes aberrant accumulation in the endoplasmic reticulum instead of localization to the plasma membrane (Roselli et al. 2004. PubMed ID: 14675423).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-179561327-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3064145.Status of the report is criteria_provided_single_submitter, 1 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.
• PP5: Variant 1-179561327-C-T is Pathogenic according to our data. Variant chr1-179561327-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5360.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.413G>A	p.Arg138Gln	missense	Exon 3 of 8	NP_055440.1	Q9NP85-1
	NPHS2	NM_001297575.2		c.413G>A	p.Arg138Gln	missense	Exon 3 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.413G>A	p.Arg138Gln	missense	Exon 3 of 8	ENSP00000356587.4	Q9NP85-1
	NPHS2	ENST00000367616.4	TSL:1	c.413G>A	p.Arg138Gln	missense	Exon 3 of 7	ENSP00000356588.4	Q9NP85-2
	NPHS2	ENST00000902256.1		c.275-1566G>A		intron	N/A	ENSP00000572315.1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.0110

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: 0.000897

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000597 AC: 150 AN: 251306 AF XY: 0.000685

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000826 AC: 1207 AN: 1461038 Hom.: 0 Cov.: 29 AF XY: 0.000783 AC XY: 569 AN XY: 726904

African (AFR) AF: 0.000149 AC: 5 AN: 33466

American (AMR) AF: 0.0000671 AC: 3 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86246

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00104 AC: 1155 AN: 1111268

Other (OTH) AF: 0.000580 AC: 35 AN: 60362

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.000512 AC XY: 38 AN XY: 74264

African (AFR) AF: 0.000193 AC: 8 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000811 Hom.: 0

Bravo AF: 0.000586

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000675 AC: 82

EpiCase AF: 0.000709

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	1	-	Nephrotic syndrome, type 2 (12)
10	-	-	not provided (10)
2	-	-	Nephrotic syndrome (2)
1	-	-	Chronic kidney disease (1)
1	-	-	Nephrotic range proteinuria (1)
1	-	-	NPHS2-related disorder (1)
1	-	-	See cases (1)
1	-	-	Steroid-resistant nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.86
MPC		0.99
ClinPred		0.18	T
GERP RS		5.8
Varity_R		0.94
gMVP		0.95
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: 34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74315342; hg19: chr1-179530462;