rs80358262
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006432.5(NPC2):c.133C>T(p.Gln45Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NPC2
NM_006432.5 stop_gained
NM_006432.5 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 3.06
Genes affected
NPC2 (HGNC:14537): (NPC intracellular cholesterol transporter 2) This gene encodes a protein containing a lipid recognition domain. The encoded protein may function in regulating the transport of cholesterol through the late endosomal/lysosomal system. Mutations in this gene have been associated with Niemann-Pick disease, type C2 and frontal lobe atrophy. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 14-74486386-G-A is Pathogenic according to our data. Variant chr14-74486386-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC2 | NM_006432.5 | c.133C>T | p.Gln45Ter | stop_gained | 2/5 | ENST00000555619.6 | |
NPC2 | NM_001363688.1 | c.133C>T | p.Gln45Ter | stop_gained | 2/4 | ||
NPC2 | NM_001375440.1 | c.133C>T | p.Gln45Ter | stop_gained | 2/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC2 | ENST00000555619.6 | c.133C>T | p.Gln45Ter | stop_gained | 2/5 | 1 | NM_006432.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1453886Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 722134
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
AN:
1453886
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Cov.:
31
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AC XY:
0
AN XY:
722134
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Niemann-Pick disease, type C2 Pathogenic:3Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 03, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 24, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 21455). This premature translational stop signal has been observed in individual(s) with Niemann-Pick type C (PMID: 15937921). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln45*) in the NPC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPC2 are known to be pathogenic (PMID: 25145893). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 17, 2018 | The NPC2 c.133C>T (p.Gln45Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Gln45Ter variant has been reported in at least two studies in which it is found in a homozygous state in a total of two patients with Niemann-Pick Disease type C (NPC) (Chikh et al. 2005; Boenzi et al. 2014). Control data is unavailable for the p.Gln45Ter variant, which is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium or the Genome Aggregation Database, in a region of good sequence coverage, and hence is presumed to be rare. Functional studies using patient-derived fibroblasts isolated from two patients demonstrated that the p.Gln45Ter variant affected intracellular cholesterol processing to the degree previously associated with classic NPC (Chikh et al. 2005; Boenzi et al. 2014). Additionally, LC-MS/MS testing of the p.Gln45Ter patient-derived plasma oxysterols revealed pathogenic levels of C-triol and 7-KC compared to normal controls (Boenzi et al. 2014). Based on the collective evidence, the p.Gln45Ter variant is classified as likely pathogenic for Niemann-Pick Disease type C. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Niemann-Pick disease, type C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 23, 2019 | Variant summary: NPC2 c.133C>T (p.Gln45X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory. The variant was absent in 236558 control chromosomes (gnomAD). The variant, c.133C>T, has been reported in the literature in two homozygous individuals affected with Niemann-Pick Disease Type C (Vanier_2004, Chikh_2005, Boenzi_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at