rs74315345

Variant names:

• chr1-179575591-C-A
• rs74315345
• NM_014625.4:c.274G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-179575591-C-A
• chr1-179575591-C-G
• chr1-179575591-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_014625.4(NPHS2):​c.274G>T​(p.Gly92Cys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G92D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPHS2 NM_014625.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.33
• Publications: 15 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: Likely_pathogenic. The variant received 8 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-179575591-C-A is Pathogenic according to our data. Variant chr1-179575591-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 5366.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	NM_014625.4	MANE Select	c.274G>T	p.Gly92Cys	missense splice_region	Exon 1 of 8	NP_055440.1
	NPHS2	NM_001297575.2		c.274G>T	p.Gly92Cys	missense splice_region	Exon 1 of 7	NP_001284504.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	ENST00000367615.9	TSL:1 MANE Select	c.274G>T	p.Gly92Cys	missense splice_region	Exon 1 of 8	ENSP00000356587.4
	NPHS2	ENST00000367616.4	TSL:1	c.274G>T	p.Gly92Cys	missense splice_region	Exon 1 of 7	ENSP00000356588.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Nephrotic syndrome, type 2 Pathogenic:1

Apr 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.77		Loss of disorder (P = 0.0425)
MVP		0.95
MPC		0.94
ClinPred		1.0	D
GERP RS		4.1
PromoterAI		-0.14	Neutral
Varity_R		0.80
gMVP		0.84
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.52		Position offset: -36

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

Other links and lift over

dbSNP: rs74315345; hg19: chr1-179544726; COSMIC: COSV62635220; COSMIC: COSV62635220;