rs73392120
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_000271.5(NPC1):c.2514+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,613,974 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.014 ( 36 hom., cov: 32)
Exomes 𝑓: 0.0014 ( 60 hom. )
Consequence
NPC1
NM_000271.5 splice_donor_region, intron
NM_000271.5 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00002474
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 -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
?
Variant 18-23541062-G-A is Benign according to our data. Variant chr18-23541062-G-A is described in ClinVar as [Benign]. Clinvar id is 92707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23541062-G-A is described in Lovd as [Benign]. Variant chr18-23541062-G-A is described in Lovd as [Likely_benign].
BA1
?
GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.2514+6C>T | splice_donor_region_variant, intron_variant | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.2514+6C>T | splice_donor_region_variant, intron_variant | 1 | NM_000271.5 | P1 | |||
NPC1 | ENST00000591051.1 | c.1592+6C>T | splice_donor_region_variant, intron_variant | 2 | |||||
NPC1 | ENST00000540608.5 | n.2428+6C>T | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 2 | |||||
NPC1 | ENST00000586718.1 | n.305+6C>T | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0137 AC: 2084AN: 152068Hom.: 36 Cov.: 32
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GnomAD3 exomes AF: 0.00388 AC: 975AN: 251426Hom.: 22 AF XY: 0.00269 AC XY: 366AN XY: 135882
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GnomAD4 exome AF: 0.00142 AC: 2070AN: 1461786Hom.: 60 Cov.: 32 AF XY: 0.00116 AC XY: 846AN XY: 727200
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GnomAD4 genome ? AF: 0.0137 AC: 2085AN: 152188Hom.: 36 Cov.: 32 AF XY: 0.0126 AC XY: 936AN XY: 74394
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ClinVar
Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Niemann-Pick disease, type C1 Benign:3
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 29, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 07, 2018 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at