rs776859868
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_014625.4(NPHS2):c.965G>T(p.Arg322Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R322P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_014625.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPHS2 | ENST00000367615.9 | c.965G>T | p.Arg322Leu | missense_variant | Exon 8 of 8 | 1 | NM_014625.4 | ENSP00000356587.4 | ||
AXDND1 | ENST00000367618.8 | c.3032-3152C>A | intron_variant | Intron 25 of 25 | 1 | NM_144696.6 | ENSP00000356590.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251048Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135638
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461838Hom.: 0 Cov.: 42 AF XY: 0.00000138 AC XY: 1AN XY: 727218
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
NPHS2-related disorder Uncertain:1
The NPHS2 c.965G>T variant is predicted to result in the amino acid substitution p.Arg322Leu. To our knowledge, this variant has not been reported in the literature. However, other amino acid substitutions at this position have been reported in individuals with nephrotic syndrome (p.Arg322Gln in Berdeli et al. 2007. PubMed ID: 17899208; p.Arg322Pro in Sharma et al. 2008. PubMed ID: 19484379; p.Arg322Gly in Basiratnia et al. 2013. PubMed ID: 24072147). The c.965G>T (p.Arg322Leu) variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at