rs1410592

Variant names:

• chr1-179551371-G-A
• rs1410592
• NM_014625.4:c.954C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-179551371-G-A
• chr1-179551371-G-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_014625.4(NPHS2):​c.954C>T​(p.Ala318Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.618 in 1,613,796 control chromosomes in the GnomAD database, including 308,950 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28814 hom., cov: 31)
  • Exomes 𝑓: 0.62 (280136 hom.)
• Consequence: NPHS2 NM_014625.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.562
• Publications: 44 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 1-179551371-G-A is Benign according to our data. Variant chr1-179551371-G-A is described in ClinVar as Benign. ClinVar VariationId is 260432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.562 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.954C>T	p.Ala318Ala	synonymous_variant	Exon 8 of 8	ENST00000367615.9	NP_055440.1
AXDND1	NM_144696.6	c.3032-3141G>A		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.954C>T	p.Ala318Ala	synonymous_variant	Exon 8 of 8	1	NM_014625.4	ENSP00000356587.4
AXDND1	ENST00000367618.8	c.3032-3141G>A		intron_variant	Intron 25 of 25	1	NM_144696.6	ENSP00000356590.3

Frequencies

GnomAD3 genomes AF: 0.614 AC: 93257 AN: 151874 Hom.: 28786 Cov.: 31

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.638

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.619

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.608

GnomAD2 exomes AF: 0.619 AC: 155359 AN: 250964 AF XY: 0.618

Gnomad AFR exome AF: 0.600

Gnomad AMR exome AF: 0.665

Gnomad ASJ exome AF: 0.659

Gnomad EAS exome AF: 0.473

Gnomad FIN exome AF: 0.622

Gnomad NFE exome AF: 0.631

Gnomad OTH exome AF: 0.624

GnomAD4 exome AF: 0.618 AC: 903486 AN: 1461802 Hom.: 280136 Cov.: 60 AF XY: 0.618 AC XY: 449545 AN XY: 727192

African (AFR) AF: 0.600 AC: 20089 AN: 33480

American (AMR) AF: 0.663 AC: 29644 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 17217 AN: 26134

East Asian (EAS) AF: 0.507 AC: 20119 AN: 39696

South Asian (SAS) AF: 0.602 AC: 51932 AN: 86254

European-Finnish (FIN) AF: 0.622 AC: 33209 AN: 53418

Middle Eastern (MID) AF: 0.653 AC: 3755 AN: 5750

European-Non Finnish (NFE) AF: 0.621 AC: 690220 AN: 1111962

Other (OTH) AF: 0.618 AC: 37301 AN: 60388

GnomAD4 genome AF: 0.614 AC: 93340 AN: 151994 Hom.: 28814 Cov.: 31 AF XY: 0.613 AC XY: 45530 AN XY: 74282

African (AFR) AF: 0.604 AC: 25029 AN: 41458

American (AMR) AF: 0.639 AC: 9761 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 2219 AN: 3466

East Asian (EAS) AF: 0.468 AC: 2411 AN: 5154

South Asian (SAS) AF: 0.591 AC: 2844 AN: 4810

European-Finnish (FIN) AF: 0.619 AC: 6543 AN: 10562

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.625 AC: 42480 AN: 67946

Other (OTH) AF: 0.608 AC: 1286 AN: 2114

Alfa AF: 0.626 Hom.: 124683

Bravo AF: 0.616

Asia WGS AF: 0.565 AC: 1966 AN: 3478

EpiCase AF: 0.627

EpiControl AF: 0.628

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 86% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 80. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The NPHS2 c.954C>T (p.Ala318Ala) variant involves the alteration of a non-conserved nucleotide resulting in a synonymous change. One in silico tool (MutationTaster) predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing, howevere these predictions are yet to be confirmed by the functional studies. This variant was found in 75096/121278 control chromosomes (including 23360 homozygotes) at a frequency of 0.6192055, which is approximately 350 times the estimated maximal expected allele frequency of a pathogenic NPHS2 variant (0.0017678), suggesting this variant is a common benign polymorphism. The variant of interest has also been cited as a polymorphism in published reports (Rachmadi_2015). Taken together, this variant is classified as Benign. -

Oct 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephrotic syndrome, type 2 Benign:2

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. -

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Steroid-resistant nephrotic syndrome Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.17
DANN	Benign	0.63
PhyloP100		-0.56
Mutation Taster		=98/2	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: rs1410592; hg19: chr1-179520506; COSMIC: COSV62634578; COSMIC: COSV62634578;