rs104894457
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_006432.5(NPC2):c.436C>T(p.Gln146*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,830 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 Likely pathogenic (★★).
Frequency
Consequence
NM_006432.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPC2 | NM_006432.5 | c.436C>T | p.Gln146* | stop_gained | Exon 4 of 5 | ENST00000555619.6 | NP_006423.1 | |
NPC2 | NM_001363688.1 | c.436C>T | p.Gln146* | stop_gained | Exon 4 of 4 | NP_001350617.1 | ||
NPC2 | NM_001375440.1 | c.364-419C>T | intron_variant | Intron 3 of 3 | NP_001362369.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460830Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726810
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C2 Pathogenic:2
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Niemann-Pick disease, type C Pathogenic:1
Variant summary: NPC2 c.436C>T (p.Gln146X) results in a premature termination codon, predicted to cause a truncation of the encoded protein. The variant was absent in 251468 control chromosomes (gnomAD). c.436C>T has been reported in the literature in the homozygous state in multiple individuals affected with Niemann-Pick Disease Type C (e.g. Millat_2005, Reunert_2015, Dardis_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Verot_2007). In fibroblasts derived from a homozygous patient, RT-PCR analysis indicated that the variant transcript was not subjected to nonsense mediated decay, however NPC2 protein was not detected by both Western blot and immunocytochemical approahes, suggesting that the variant results in an unstable protein. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely 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