chr1-179550915-T-C

Variant names:

• chr1-179550915-T-C
• rs2274622
• NM_014625.4:c.*258A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014625.4(NPHS2):​c.*258A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 512,930 control chromosomes in the GnomAD database, including 20,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4898 hom., cov: 32)
  • Exomes 𝑓: 0.29 (15691 hom.)
• Consequence: NPHS2 NM_014625.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.259
• 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]

AXDND1 (HGNC:26564): (axonemal dynein light chain domain containing 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-179550915-T-C is Benign according to our data. Variant chr1-179550915-T-C is described in ClinVar as [Benign]. Clinvar id is 224485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.*258A>G		3_prime_UTR_variant	Exon 8 of 8	ENST00000367615.9	NP_055440.1
AXDND1	NM_144696.6	c.3032-3597T>C		intron_variant	Intron 25 of 25	ENST00000367618.8	NP_653297.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9	c.*258A>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_014625.4	ENSP00000356587.4
AXDND1	ENST00000367618.8	c.3032-3597T>C		intron_variant	Intron 25 of 25	1	NM_144696.6	ENSP00000356590.3

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36751 AN: 151984 Hom.: 4892 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.266

GnomAD4 exome AF: 0.286 AC: 103298 AN: 360826 Hom.: 15691 Cov.: 4 AF XY: 0.290 AC XY: 55549 AN XY: 191260

African (AFR) AF: 0.130 AC: 1377 AN: 10584

American (AMR) AF: 0.295 AC: 4674 AN: 15830

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 2718 AN: 10982

East Asian (EAS) AF: 0.383 AC: 8613 AN: 22502

South Asian (SAS) AF: 0.341 AC: 14657 AN: 42920

European-Finnish (FIN) AF: 0.229 AC: 4520 AN: 19698

Middle Eastern (MID) AF: 0.322 AC: 496 AN: 1542

European-Non Finnish (NFE) AF: 0.280 AC: 60447 AN: 216230

Other (OTH) AF: 0.282 AC: 5796 AN: 20538

GnomAD4 genome AF: 0.242 AC: 36768 AN: 152104 Hom.: 4898 Cov.: 32 AF XY: 0.243 AC XY: 18041 AN XY: 74352

African (AFR) AF: 0.127 AC: 5274 AN: 41518

American (AMR) AF: 0.302 AC: 4617 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 823 AN: 3470

East Asian (EAS) AF: 0.357 AC: 1840 AN: 5160

South Asian (SAS) AF: 0.351 AC: 1690 AN: 4818

European-Finnish (FIN) AF: 0.231 AC: 2451 AN: 10592

Middle Eastern (MID) AF: 0.308 AC: 90 AN: 292

European-Non Finnish (NFE) AF: 0.281 AC: 19103 AN: 67966

Other (OTH) AF: 0.271 AC: 572 AN: 2110

Alfa AF: 0.273 Hom.: 18749

Bravo AF: 0.241

Asia WGS AF: 0.374 AC: 1301 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 2 Benign:3

Jan 12, 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. -

Jan 01, 2016

Human Genetics Disease in Children – Taif University, Taif University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Aug 20, 2019

GeneDx

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.7
DANN	Benign	0.73
PhyloP100		0.26
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: rs2274622; hg19: chr1-179520050;