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GeneBe

rs61747728

chr1-179557079-C-Gchr1-179557079-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2_SupportingPM5PP3_Moderate

The NM_014625(NPHS2):c.686G>C(p.Arg229Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic 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. R229Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

NPHS2
NM_014625 missense

Scores

11
6
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.46

Links

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
?
In a topological_domain Cytoplasmic (size 259) in uniprot entity PODO_HUMAN there are 125 pathogenic changes around while only 3 benign (98%) in NM_014625
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 32.
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr1-179557079-C-T is described in ClinVar as [Conflicting_interpretations_of_pathogenicity]. Clinvar id is 5370. Status of the report is criteria_provided_conflicting_interpretations, 1 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=4, Uncertain_significance=8, Benign=1}.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPHS2NM_014625.4 linkuse as main transcriptc.686G>C p.Arg229Pro missense_variant 5/8 ENST00000367615.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPHS2ENST00000367615.9 linkuse as main transcriptc.686G>C p.Arg229Pro missense_variant 5/81 NM_014625.4 P1Q9NP85-1
NPHS2ENST00000367616.4 linkuse as main transcriptc.535-2548G>C intron_variant 1 Q9NP85-2

Frequencies

GnomAD3 genomes
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.37
Cadd
Pathogenic
27
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
D
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.89
D
M_CAP
Pathogenic
0.46
D
MetaRNN
Pathogenic
0.93
D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Uncertain
2.4
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.47
T
PROVEAN
Pathogenic
-4.7
D
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.017
D
Polyphen
1.0
D
Vest4
0.74
MutPred
0.76
Loss of MoRF binding (P = 0.0255);
MVP
0.92
MPC
1.1
ClinPred
0.99
D
GERP RS
5.9
Varity_R
0.98
gMVP
0.87

Splicing

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: rs61747728; hg19: chr1-179526214;