rs80358264
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_006432.5(NPC2):āc.295T>Cā(p.Cys99Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,014 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 Pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C99F) has been classified as Uncertain significance.
Frequency
Consequence
NM_006432.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC2 | NM_006432.5 | c.295T>C | p.Cys99Arg | missense_variant | 3/5 | ENST00000555619.6 | |
NPC2 | NM_001363688.1 | c.295T>C | p.Cys99Arg | missense_variant | 3/4 | ||
NPC2 | NM_001375440.1 | c.295T>C | p.Cys99Arg | missense_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC2 | ENST00000555619.6 | c.295T>C | p.Cys99Arg | missense_variant | 3/5 | 1 | NM_006432.5 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251486Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135920
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727244
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74320
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C2 Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 03, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 99 of the NPC2 protein (p.Cys99Arg). This variant is present in population databases (rs80358264, gnomAD 0.006%). This missense change has been observed in individual(s) with Niemann-Pick Type C (PMID: 15937921, 22676771). ClinVar contains an entry for this variant (Variation ID: 21458). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NPC2 function (PMID: 15937921). For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Niemann-Pick disease, type C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 30, 2023 | Variant summary: NPC2 c.295T>C (p.Cys99Arg) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the MD-2-related lipid-recognition domain (IPR003172) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251486 control chromosomes (gnomAD). c.295T>C has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (Chikh_2005, Heron_2012). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a misfolded protein that localizes to the endoplasmic reticulum and is unable to rescue cholesterol storage in NPC2-null cells (Chikh_2005). The following publications have been ascertained in the context of this evaluation (PMID: 15937921, 22676771). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at