NM_014625.4:c.288C>T

Variant names:

• chr1-179564780-G-A
• rs3738423
• NM_014625.4:c.288C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014625.4(NPHS2):​c.288C>T​(p.Ser96Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0842 in 1,612,474 control chromosomes in the GnomAD database, including 6,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (615 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5692 hom.)
• Consequence: NPHS2 NM_014625.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.42
• Publications: 20 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-179564780-G-A is Benign according to our data. Variant chr1-179564780-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.42 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0857 is higher than 0.05.

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.288C>T	p.Ser96Ser	synonymous	Exon 2 of 8	NP_055440.1	Q9NP85-1
	NPHS2	NM_001297575.2		c.288C>T	p.Ser96Ser	synonymous	Exon 2 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.288C>T	p.Ser96Ser	synonymous	Exon 2 of 8	ENSP00000356587.4	Q9NP85-1
	NPHS2	ENST00000367616.4	TSL:1	c.288C>T	p.Ser96Ser	synonymous	Exon 2 of 7	ENSP00000356588.4	Q9NP85-2
	NPHS2	ENST00000902256.1		c.275-5019C>T		intron	N/A	ENSP00000572315.1

Frequencies

GnomAD3 genomes AF: 0.0841 AC: 12797 AN: 152076 Hom.: 615 Cov.: 32

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.0596

Gnomad ASJ AF: 0.0747

Gnomad EAS AF: 0.0889

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0852

Gnomad OTH AF: 0.0784

GnomAD2 exomes AF: 0.0734 AC: 18446 AN: 251188 AF XY: 0.0706

Gnomad AFR exome AF: 0.0896

Gnomad AMR exome AF: 0.0355

Gnomad ASJ exome AF: 0.0634

Gnomad EAS exome AF: 0.0939

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.0851

Gnomad OTH exome AF: 0.0760

GnomAD4 exome AF: 0.0842 AC: 122921 AN: 1460280 Hom.: 5692 Cov.: 31 AF XY: 0.0815 AC XY: 59206 AN XY: 726504

African (AFR) AF: 0.0846 AC: 2830 AN: 33458

American (AMR) AF: 0.0375 AC: 1678 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0644 AC: 1682 AN: 26126

East Asian (EAS) AF: 0.0675 AC: 2679 AN: 39686

South Asian (SAS) AF: 0.0138 AC: 1186 AN: 86240

European-Finnish (FIN) AF: 0.131 AC: 6990 AN: 53408

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5764

European-Non Finnish (NFE) AF: 0.0908 AC: 100818 AN: 1110562

Other (OTH) AF: 0.0825 AC: 4980 AN: 60340

GnomAD4 genome AF: 0.0841 AC: 12803 AN: 152194 Hom.: 615 Cov.: 32 AF XY: 0.0832 AC XY: 6191 AN XY: 74416

African (AFR) AF: 0.0881 AC: 3657 AN: 41516

American (AMR) AF: 0.0595 AC: 910 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0747 AC: 259 AN: 3468

East Asian (EAS) AF: 0.0891 AC: 462 AN: 5186

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4820

European-Finnish (FIN) AF: 0.131 AC: 1381 AN: 10576

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0852 AC: 5794 AN: 68014

Other (OTH) AF: 0.0781 AC: 165 AN: 2114

Alfa AF: 0.0799 Hom.: 497

Bravo AF: 0.0798

Asia WGS AF: 0.0380 AC: 133 AN: 3478

EpiCase AF: 0.0764

EpiControl AF: 0.0756

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Nephrotic syndrome, type 2 (3)
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Steroid-resistant nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.3
DANN	Benign	0.22
PhyloP100		-2.4
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs3738423; hg19: chr1-179533915; COSMIC: COSV62635462;