18-23560296-CATG-C
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM4_SupportingPP3PP5
The NM_000271.5(NPC1):c.813_815delCAT(p.Ile271del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
NPC1
NM_000271.5 disruptive_inframe_deletion
NM_000271.5 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.32
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 Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000271.5. Strenght limited to Supporting due to length of the change: 1aa.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 18-23560296-CATG-C is Pathogenic according to our data. Variant chr18-23560296-CATG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449503.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
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NPC1 | NM_000271.5 | c.813_815delCAT | p.Ile271del | disruptive_inframe_deletion | 6/25 | ENST00000269228.10 | NP_000262.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.813_815delCAT | p.Ile271del | disruptive_inframe_deletion | 6/25 | 1 | NM_000271.5 | ENSP00000269228.4 | ||
NPC1 | ENST00000591051.1 | c.42_44delCAT | p.Ile14del | disruptive_inframe_deletion | 1/18 | 2 | ENSP00000467636.1 | |||
NPC1 | ENST00000540608.5 | n.727_729delCAT | non_coding_transcript_exon_variant | 4/16 | 2 |
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GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461872Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727236
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Dec 28, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2017 | The c.813_815delCAT variant in the NPC1 gene has been reported in an individual with Neiman-Pick C disease with impaired cholesterol esterification rate who also possessed a second variant in the NPC1 gene (Sun et al.,2001). The c.813_815delCAT variant causes an in-frame deletion of one amino acid, Isoleucine 271, denotedp.Ile271del. This amino acid deletion occurs at a position that is conserved across species. The c.813_815delCATvariant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; ExomeVariant Server).We interpret c.813_815delCAT as a likely pathogenic variant. - |
Niemann-Pick disease, type C1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 25, 2022 | This variant, c.813_815del, results in the deletion of 1 amino acid(s) of the NPC1 protein (p.Ile271del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Niemann-Pick disease type C (PMID: 11349231, 31130284). ClinVar contains an entry for this variant (Variation ID: 449503). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Counsyl | Nov 17, 2017 | - - |
Niemann-Pick disease, type C Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 04, 2022 | Variant summary: NPC1 c.813_815delCAT (p.Ile271del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 250742 control chromosomes. c.813_815delCAT has been reported in the literature in individuals affected with features of Niemann-Pick Disease Type C and in settings of clinical exome sequencing in an affected consanguineous population (example, Sun_2001, Monies_2019). 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (LP, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
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DS_DG_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at