rs2285450

Variant names:

• chr19-35851365-G-A
• rs2285450
• NM_004646.4:c.294C>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_004646.4(NPHS1):​c.294C>T​(p.Ile98Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,202 control chromosomes in the GnomAD database, including 1,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (365 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (818 hom.)
• Consequence: NPHS1 NM_004646.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.365
• Publications: 7 publications found

Genes affected

NPHS1 (HGNC:7908): (NPHS1 adhesion molecule, nephrin) This gene encodes a member of the immunoglobulin family of cell adhesion molecules that functions in the glomerular filtration barrier in the kidney. The gene is primarily expressed in renal tissues, and the protein is a type-1 transmembrane protein found at the slit diaphragm of glomerular podocytes. The slit diaphragm is thought to function as an ultrafilter to exclude albumin and other plasma macromolecules in the formation of urine. Mutations in this gene result in Finnish-type congenital nephrosis 1, characterized by severe proteinuria and loss of the slit diaphragm and foot processes.[provided by RefSeq, Oct 2009]

KIRREL2 (HGNC:18816): (kirre like nephrin family adhesion molecule 2) This gene encodes a type I transmembrane protein and member of the immunoglobulin superfamily of cell adhesion molecules. The encoded protein localizes to adherens junctions in pancreatic beta cells and regulates insulin secretion. Autoantibodies against the encoded protein have been detected in serum from patients with type 1 diabetes. This gene may also play a role in glomerular development and decreased expression of this gene has been observed in human glomerular diseases. This gene and the related opposite-strand gene nephrin (GeneID: 527362) are regulated by a bidirectional promoter. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 19-35851365-G-A is Benign according to our data. Variant chr19-35851365-G-A is described in ClinVar as Benign. ClinVar VariationId is 259492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.365 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.294C>T	p.Ile98Ile	synonymous_variant	Exon 3 of 29	ENST00000378910.10	NP_004637.1
KIRREL2	XM_011527362.2	c.-542G>A		upstream_gene_variant			XP_011525664.1
KIRREL2	XM_011527363.2	c.-533G>A		upstream_gene_variant			XP_011525665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.294C>T	p.Ile98Ile	synonymous_variant	Exon 3 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.294C>T	p.Ile98Ile	synonymous_variant	Exon 3 of 28	5		ENSP00000343634.5

Frequencies

GnomAD3 genomes AF: 0.0408 AC: 6201 AN: 152132 Hom.: 345 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0229

GnomAD2 exomes AF: 0.0217 AC: 5349 AN: 246642 AF XY: 0.0190

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.00680

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.133

Gnomad FIN exome AF: 0.000284

Gnomad NFE exome AF: 0.000911

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.00949 AC: 13861 AN: 1460952 Hom.: 818 Cov.: 35 AF XY: 0.00911 AC XY: 6624 AN XY: 726750

African (AFR) AF: 0.133 AC: 4462 AN: 33470

American (AMR) AF: 0.00738 AC: 329 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 340 AN: 26108

East Asian (EAS) AF: 0.148 AC: 5888 AN: 39662

South Asian (SAS) AF: 0.0130 AC: 1119 AN: 86168

European-Finnish (FIN) AF: 0.000244 AC: 13 AN: 53174

Middle Eastern (MID) AF: 0.0111 AC: 64 AN: 5768

European-Non Finnish (NFE) AF: 0.000486 AC: 540 AN: 1111666

Other (OTH) AF: 0.0183 AC: 1106 AN: 60360

GnomAD4 genome AF: 0.0411 AC: 6250 AN: 152250 Hom.: 365 Cov.: 32 AF XY: 0.0409 AC XY: 3043 AN XY: 74456

African (AFR) AF: 0.122 AC: 5070 AN: 41536

American (AMR) AF: 0.0172 AC: 263 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.134 AC: 691 AN: 5170

South Asian (SAS) AF: 0.0180 AC: 87 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68010

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0201 Hom.: 91

Bravo AF: 0.0472

Asia WGS AF: 0.0640 AC: 221 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 23, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26147534) -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Finnish congenital nephrotic syndrome Benign:1

Nov 25, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Congenital nephrotic syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.6
DANN	Benign	0.91
PhyloP100		-0.36
PromoterAI		0.0073	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs2285450; hg19: chr19-36342267; COSMIC: COSV62288051; COSMIC: COSV62288051;