chr1-179575915-C-A

Variant names:

• chr1-179575915-C-A
• rs12406197
• NM_014625.4:c.-51G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014625.4(NPHS2):​c.-51G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 1,358,458 control chromosomes in the GnomAD database, including 47,137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4506 hom., cov: 34)
  • Exomes 𝑓: 0.26 (42631 hom.)
• Consequence: NPHS2 NM_014625.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:12
• Conservation: PhyloP100: -1.14

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 1-179575915-C-A is Benign according to our data. Variant chr1-179575915-C-A is described in ClinVar as [Benign]. Clinvar id is 225144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179575915-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.-51G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	ENST00000367615.9	NP_055440.1
NPHS2	NM_014625.4	c.-51G>T		5_prime_UTR_variant	Exon 1 of 8	ENST00000367615.9	NP_055440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9	c.-51G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	1	NM_014625.4	ENSP00000356587.4
NPHS2	ENST00000367616.4	c.-51G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	1		ENSP00000356588.4
NPHS2	ENST00000367615.9	c.-51G>T		5_prime_UTR_variant	Exon 1 of 8	1	NM_014625.4	ENSP00000356587.4
NPHS2	ENST00000367616.4	c.-51G>T		5_prime_UTR_variant	Exon 1 of 7	1		ENSP00000356588.4

Frequencies

GnomAD3 genomes AF: 0.237 AC: 35998 AN: 152074 Hom.: 4502 Cov.: 34

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.232

GnomAD3 exomes AF: 0.255 AC: 5501 AN: 21614 Hom.: 753 AF XY: 0.254 AC XY: 3133 AN XY: 12342

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.374

Gnomad EAS exome AF: 0.0981

Gnomad SAS exome AF: 0.199

Gnomad FIN exome AF: 0.325

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.263 AC: 316772 AN: 1206276 Hom.: 42631 Cov.: 30 AF XY: 0.263 AC XY: 153097 AN XY: 583210

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.299

Gnomad4 ASJ exome AF: 0.340

Gnomad4 EAS exome AF: 0.129

Gnomad4 SAS exome AF: 0.221

Gnomad4 FIN exome AF: 0.308

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.251

GnomAD4 genome AF: 0.237 AC: 36016 AN: 152182 Hom.: 4506 Cov.: 34 AF XY: 0.238 AC XY: 17719 AN XY: 74386

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.340

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.209

Gnomad4 FIN AF: 0.306

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.229

Alfa AF: 0.259 Hom.: 636

Bravo AF: 0.232

Asia WGS AF: 0.161 AC: 558 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 41% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 38. Only high quality variants are reported. -

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephrotic syndrome, type 2 Pathogenic:1 Benign:2

Jan 01, 2016

Human Genetics Disease in Children – Taif University, Taif University

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 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. -

not provided Benign:3

Nov 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16900088, 30793612) -

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

NPHS2-related disorder Benign:1

Feb 23, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Focal segmental glomerulosclerosis Benign:1

Sep 27, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.3
DANN	Benign	0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs12406197; hg19: chr1-179545050; COSMIC: COSV62635817; COSMIC: COSV62635817;