1-179561279-G-GT

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_014625.4(NPHS2):​c.451+9dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00046 in 1,605,678 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 5 hom., cov: 32)
Exomes 𝑓: 0.00028 ( 4 hom. )

Consequence

NPHS2
NM_014625.4 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.873
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP6
Variant 1-179561279-G-GT is Benign according to our data. Variant chr1-179561279-G-GT is described in ClinVar as [Likely_benign]. Clinvar id is 260427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPHS2NM_014625.4 linkc.451+9dupA intron_variant Intron 3 of 7 ENST00000367615.9 NP_055440.1 Q9NP85-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPHS2ENST00000367615.9 linkc.451+9_451+10insA intron_variant Intron 3 of 7 1 NM_014625.4 ENSP00000356587.4 Q9NP85-1
NPHS2ENST00000367616.4 linkc.451+9_451+10insA intron_variant Intron 3 of 6 1 ENSP00000356588.4 Q9NP85-2

Frequencies

GnomAD3 genomes
AF:
0.00216
AC:
328
AN:
152066
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00734
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000621
AC:
156
AN:
251324
Hom.:
0
AF XY:
0.000523
AC XY:
71
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.00776
Gnomad AMR exome
AF:
0.000550
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.000490
GnomAD4 exome
AF:
0.000283
AC:
412
AN:
1453494
Hom.:
4
Cov.:
29
AF XY:
0.000238
AC XY:
172
AN XY:
723778
show subpopulations
Gnomad4 AFR exome
AF:
0.00840
Gnomad4 AMR exome
AF:
0.000425
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000349
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000489
Gnomad4 OTH exome
AF:
0.000766
GnomAD4 genome
AF:
0.00215
AC:
327
AN:
152184
Hom.:
5
Cov.:
32
AF XY:
0.00200
AC XY:
149
AN XY:
74426
show subpopulations
Gnomad4 AFR
AF:
0.00730
Gnomad4 AMR
AF:
0.00131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000825
Hom.:
0
Bravo
AF:
0.00234
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 20, 2024Variant summary: NPHS2 c.451+9dupA alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00062 in 251324 control chromosomes, predominantly at a frequency of 0.0078 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4.41 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPHS2 causing Nephrotic Syndrome, Type 2 phenotype (0.0018). To our knowledge, no occurrence of c.451+9dupA in individuals affected with Nephrotic Syndrome, Type 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 260427). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Likely benign, criteria provided, single submitterclinical testingAthena DiagnosticsDec 02, 2016- -
Nephrotic syndrome, type 2 Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 28, 2021- -
Kidney disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenDec 08, 2021- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 24, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs542240453; hg19: chr1-179530414; API