rs1555633326
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000271.5(NPC1):c.2683_2684insG(p.Glu895GlyfsTer23) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E895E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000271.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.2683_2684insG | p.Glu895GlyfsTer23 | frameshift_variant | 18/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.2683_2684insG | p.Glu895GlyfsTer23 | frameshift_variant | 18/25 | 1 | NM_000271.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461888Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 727248
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 09, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 08, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 551834). This variant is also known as c.2683insG (fs917X). This premature translational stop signal has been observed in individual(s) with Niemann-Pick Type C (PMID: 26981555). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu895Glyfs*23) in the NPC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPC1 are known to be pathogenic (PMID: 9211850). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 12, 2022 | Observed with a second pathogenic NPC1 variant in a patient from the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Reunert et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26981555) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at