NM_014625.4:c.304G>A

Variant names:

• chr1-179564764-C-T
• rs1553315157
• NM_014625.4:c.304G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_014625.4(NPHS2):​c.304G>A​(p.Glu102Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPHS2 NM_014625.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 5.64
• 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: 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: Uncertain_significance. The variant received 5 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 nephrotic syndrome, type 2, familial idiopathic steroid-resistant nephrotic syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.304G>A	p.Glu102Lys	missense_variant	Exon 2 of 8	ENST00000367615.9	NP_055440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9	c.304G>A	p.Glu102Lys	missense_variant	Exon 2 of 8	1	NM_014625.4	ENSP00000356587.4
NPHS2	ENST00000367616.4	c.304G>A	p.Glu102Lys	missense_variant	Exon 2 of 7	1		ENSP00000356588.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000611 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 13, 2016

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Corticosteroids response Other:1

Jan 12, 2020

Genetic Testing Lab, Ashok and Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Sciences

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

Depending upon patients response to standard corticosteroids therapy, they were classified to be either Steroid resistance(SRNS) or steroid sensitive(SSNS) likley responsive,remission within 4 weeks of corticosteroid therapy ,therefore classified as steroid sensitive nephrotic syndrome (SSNS)

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M
PhyloP100		5.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.3	N;N
REVEL	Pathogenic	0.84
Sift	Benign	0.16	T;T
Sift4G	Benign	0.53	T;T
Polyphen		1.0	D;D
Vest4		0.87
MVP		0.93
MPC		0.97
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.30
gMVP		0.92
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1553315157; hg19: chr1-179533899; COSMIC: COSV100858166;