rs80358268
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_006432.5(NPC2):c.190+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000196 in 1,583,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_006432.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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NPC2 | NM_006432.5 | c.190+5G>A | splice_region_variant, intron_variant | Intron 2 of 4 | ENST00000555619.6 | NP_006423.1 | ||
NPC2 | NM_001363688.1 | c.190+5G>A | splice_region_variant, intron_variant | Intron 2 of 3 | NP_001350617.1 | |||
NPC2 | NM_001375440.1 | c.190+5G>A | splice_region_variant, intron_variant | Intron 2 of 3 | NP_001362369.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000434 AC: 9AN: 207150Hom.: 0 AF XY: 0.0000182 AC XY: 2AN XY: 109940
GnomAD4 exome AF: 0.0000196 AC: 28AN: 1431022Hom.: 0 Cov.: 31 AF XY: 0.0000212 AC XY: 15AN XY: 708608
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74486
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C2 Pathogenic:7Other:1
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This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 14-year-old male with intellectual disability, epilepsy, similarly affected sibling -
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This sequence change falls in intron 2 of the NPC2 gene. It does not directly change the encoded amino acid sequence of the NPC2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs80358268, gnomAD 0.01%). This variant has been observed in individuals with Niemann-Pick type C disease (PMID: 11567215, 28105569). This variant is also known as IVS2+5G>A. ClinVar contains an entry for this variant (Variation ID: 8479). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in abnormal RNA spliceforms, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 11567215). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at