chr1-179557079-C-T

Variant names:

• chr1-179557079-C-T
• rs61747728
• NM_014625.4:c.686G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BS1_Supporting BS2

The NM_014625.4(NPHS2):​c.686G>A​(p.Arg229Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0348 in 1,613,872 control chromosomes in the GnomAD database, including 1,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R229R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (85 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1056 hom.)
• Consequence: NPHS2 NM_014625.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:11 B:2 O:2
• Conservation: PhyloP100: 2.46
• Publications: 179 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: Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, G2P
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.00867492).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0277 (4222/152288) while in subpopulation NFE AF = 0.0374 (2543/68022). AF 95% confidence interval is 0.0362. There are 85 homozygotes in GnomAd4. There are 2112 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 85 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	NM_014625.4	MANE Select	c.686G>A	p.Arg229Gln	missense	Exon 5 of 8	NP_055440.1
	NPHS2	NM_001297575.2		c.535-2548G>A		intron	N/A	NP_001284504.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	ENST00000367615.9	TSL:1 MANE Select	c.686G>A	p.Arg229Gln	missense	Exon 5 of 8	ENSP00000356587.4
	NPHS2	ENST00000367616.4	TSL:1	c.535-2548G>A		intron	N/A	ENSP00000356588.4
	NPHS2	ENST00000902256.1		c.509G>A	p.Arg170Gln	missense	Exon 3 of 6	ENSP00000572315.1

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 4222 AN: 152170 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.00611

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0187

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0281

Gnomad FIN AF: 0.0664

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0304 AC: 7639 AN: 250894 AF XY: 0.0313

Gnomad AFR exome AF: 0.00621

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0524

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0697

Gnomad NFE exome AF: 0.0358

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0355 AC: 51908 AN: 1461584 Hom.: 1056 Cov.: 32 AF XY: 0.0356 AC XY: 25877 AN XY: 727076

African (AFR) AF: 0.00574 AC: 192 AN: 33478

American (AMR) AF: 0.0140 AC: 626 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0485 AC: 1267 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39686

South Asian (SAS) AF: 0.0280 AC: 2415 AN: 86242

European-Finnish (FIN) AF: 0.0661 AC: 3527 AN: 53374

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5764

European-Non Finnish (NFE) AF: 0.0376 AC: 41780 AN: 1111840

Other (OTH) AF: 0.0331 AC: 2000 AN: 60376

GnomAD4 genome AF: 0.0277 AC: 4222 AN: 152288 Hom.: 85 Cov.: 32 AF XY: 0.0284 AC XY: 2112 AN XY: 74458

African (AFR) AF: 0.00609 AC: 253 AN: 41556

American (AMR) AF: 0.0186 AC: 285 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 196 AN: 3468

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.0282 AC: 136 AN: 4830

European-Finnish (FIN) AF: 0.0664 AC: 704 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0374 AC: 2543 AN: 68022

Other (OTH) AF: 0.0199 AC: 42 AN: 2112

Alfa AF: 0.0316 Hom.: 224

Bravo AF: 0.0232

TwinsUK AF: 0.0394 AC: 146

ALSPAC AF: 0.0394 AC: 152

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.0376 AC: 323

ExAC AF: 0.0291 AC: 3537

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.0356

EpiControl AF: 0.0352

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
9	6	-	Nephrotic syndrome, type 2 (15)
2	3	-	not provided (5)
-	1	1	not specified (2)
-	-	1	Focal segmental glomerulosclerosis (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	NPHS2-related disorder (1)
-	1	-	Proteinuria (1)
-	-	-	Nephrotic syndrome (1)
-	-	-	NEPHROTIC SYNDROME, TYPE 2, SUSCEPTIBILITY TO (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0087	T
MetaSVM	Uncertain	0.010	D
MutationAssessor	Benign	1.7	L
PhyloP100		2.5
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.58
Sift	Benign	0.21	T
Sift4G	Benign	0.18	T
Polyphen		0.90	P
Vest4		0.11
MPC		0.81
ClinPred		0.030	T
GERP RS		5.9
Varity_R		0.42
gMVP		0.66
Mutation Taster		=59/41	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: rs61747728; hg19: chr1-179526214; COSMIC: COSV62635238; COSMIC: COSV62635238;