rs80358266
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006432.5(NPC2):c.352G>T(p.Glu118Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000496 in 1,613,972 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
NPC2
NM_006432.5 stop_gained
NM_006432.5 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 4.87
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]
Genome browser will be placed here
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 14-74484426-C-A is Pathogenic according to our data. Variant chr14-74484426-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 8480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74484426-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC2 | NM_006432.5 | c.352G>T | p.Glu118Ter | stop_gained | 3/5 | ENST00000555619.6 | |
NPC2 | NM_001363688.1 | c.352G>T | p.Glu118Ter | stop_gained | 3/4 | ||
NPC2 | NM_001375440.1 | c.352G>T | p.Glu118Ter | stop_gained | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC2 | ENST00000555619.6 | c.352G>T | p.Glu118Ter | stop_gained | 3/5 | 1 | NM_006432.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152124Hom.: 0 Cov.: 31
GnomAD3 genomes
?
AF:
AC:
2
AN:
152124
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251482Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135916
GnomAD3 exomes
AF:
AC:
2
AN:
251482
Hom.:
AF XY:
AC XY:
0
AN XY:
135916
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461848Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727226
GnomAD4 exome
AF:
AC:
6
AN:
1461848
Hom.:
Cov.:
32
AF XY:
AC XY:
3
AN XY:
727226
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152124Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74292
GnomAD4 genome
?
AF:
AC:
2
AN:
152124
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
74292
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
?
AF:
AC:
2
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Niemann-Pick disease, type C2 Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 27, 2019 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 16, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Glu118*) 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). This variant is present in population databases (rs80358266, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease type C (PMID: 11567215, 25772320, 28808920). ClinVar contains an entry for this variant (Variation ID: 8480). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Niemann-Pick disease, type C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 04, 2020 | Variant summary: NPC2 c.352G>T (p.Glu118X) 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. The variant allele was found at a frequency of 8e-06 in 251482 control chromosomes (gnomAD). c.352G>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (e.g. Millat_2001, Topcu_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite 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
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
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