rs797044431
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_ModeratePM2PP3_ModeratePP5_Moderate
The NM_000271.5(NPC1):c.3042-2del variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
NPC1
NM_000271.5 splice_acceptor
NM_000271.5 splice_acceptor
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.01
Genes affected
NPC1 (HGNC:7897): (NPC intracellular cholesterol transporter 1) This gene encodes a large protein that resides in the limiting membrane of endosomes and lysosomes and mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. It is predicted to have a cytoplasmic C-terminus, 13 transmembrane domains, and 3 large loops in the lumen of the endosome - the last loop being at the N-terminus. This protein transports low-density lipoproteins to late endosomal/lysosomal compartments where they are hydrolized and released as free cholesterol. Defects in this gene cause Niemann-Pick type C disease, a rare autosomal recessive neurodegenerative disorder characterized by over accumulation of cholesterol and glycosphingolipids in late endosomal/lysosomal compartments.[provided by RefSeq, Aug 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.052905917 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.8, offset of -13, new splice context is: tggactctcttgacacccAGgat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 18-23536877-CT-C is Pathogenic according to our data. Variant chr18-23536877-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2963.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.3042-2del | splice_acceptor_variant | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.3042-2del | splice_acceptor_variant | 1 | NM_000271.5 | P1 | |||
NPC1 | ENST00000591051.1 | c.2120-2del | splice_acceptor_variant | 2 | |||||
NPC1 | ENST00000591075.1 | n.675-2del | splice_acceptor_variant, non_coding_transcript_variant | 4 | |||||
NPC1 | ENST00000591955.1 | n.385-2del | splice_acceptor_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Niemann-Pick disease, type C1, adult form Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1999 | - - |
Niemann-Pick disease, type C1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 17, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 13
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at