Genetic Variant NPHS2:p.Ala297Gly (chr1-179551435-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1PM5PP2BP4_Moderate

The NM_014625.4(NPHS2):c.890C>G(p.Ala297Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A297V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

NPHS2
NM_014625.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.77

Publications

0 publications found

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]

NPHS2 links:

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

AXDND1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_014625.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-179551435-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 370718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.68612 (below the threshold of 3.09). Trascript score misZ: 0.038296 (below the threshold of 3.09). GenCC associations: The gene is linked to nephrotic syndrome, type 2, familial idiopathic steroid-resistant nephrotic syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.12598273).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014625.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPHS2	NM_014625.4	MANE Select	c.890C>G	p.Ala297Gly	missense	Exon 8 of 8	NP_055440.1
AXDND1	NM_144696.6	MANE Select	c.3032-3077G>C		intron	N/A	NP_653297.3
NPHS2	NM_001297575.2		c.686C>G	p.Ala229Gly	missense	Exon 7 of 7	NP_001284504.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPHS2	ENST00000367615.9	TSL:1 MANE Select	c.890C>G	p.Ala297Gly	missense	Exon 8 of 8	ENSP00000356587.4
NPHS2	ENST00000367616.4	TSL:1	c.686C>G	p.Ala229Gly	missense	Exon 7 of 7	ENSP00000356588.4
AXDND1	ENST00000367618.8	TSL:1 MANE Select	c.3032-3077G>C		intron	N/A	ENSP00000356590.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461156

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726892

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5212

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111984

Other (OTH)

AF:

0.00

AC:

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.028

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.35

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.60

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.13

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

-2.0

PhyloP100

4.8

PrimateAI

Uncertain

0.71

PROVEAN

Benign

5.7

REVEL

Uncertain

0.42

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.23

MutPred

0.51

Loss of helix (P = 0.0626)

MVP

0.73

MPC

0.26

ClinPred

0.40

GERP RS

5.7

Varity_R

0.15

gMVP

0.75

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over