chr18-23544950-C-A
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000271.5(NPC1):c.1947+10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,415,988 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00020 ( 1 hom., cov: 27)
Exomes 𝑓: 0.000084 ( 2 hom. )
Consequence
NPC1
NM_000271.5 intron
NM_000271.5 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.104
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 Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 18-23544950-C-A is Benign according to our data. Variant chr18-23544950-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 495787.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.1947+10G>T | intron_variant | Intron 12 of 24 | ENST00000269228.10 | NP_000262.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.1947+10G>T | intron_variant | Intron 12 of 24 | 1 | NM_000271.5 | ENSP00000269228.4 | |||
NPC1 | ENST00000591051.1 | c.1023+10G>T | intron_variant | Intron 5 of 17 | 2 | ENSP00000467636.1 | ||||
NPC1 | ENST00000540608.5 | n.1861+10G>T | intron_variant | Intron 10 of 15 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000188 AC: 27AN: 143688Hom.: 1 Cov.: 27
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GnomAD3 exomes AF: 0.000119 AC: 29AN: 244166Hom.: 1 AF XY: 0.000106 AC XY: 14AN XY: 132590
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GnomAD4 exome AF: 0.0000841 AC: 107AN: 1272186Hom.: 2 Cov.: 26 AF XY: 0.0000922 AC XY: 59AN XY: 640108
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GnomAD4 genome AF: 0.000202 AC: 29AN: 143802Hom.: 1 Cov.: 27 AF XY: 0.000171 AC XY: 12AN XY: 70360
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Niemann-Pick disease, type C1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 06, 2025 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 21, 2018 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 12, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at