rs61731965
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000271.5(NPC1):c.966C>T(p.Ser322Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,614,068 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.011 ( 24 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 43 hom. )
Consequence
NPC1
NM_000271.5 synonymous
NM_000271.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.347
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 -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.53).
BP6
Variant 18-23556603-G-A is Benign according to our data. Variant chr18-23556603-G-A is described in ClinVar as [Benign]. Clinvar id is 326274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23556603-G-A is described in Lovd as [Likely_benign]. Variant chr18-23556603-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.347 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0114 (1732/152290) while in subpopulation AFR AF= 0.0387 (1606/41550). AF 95% confidence interval is 0.0371. There are 24 homozygotes in gnomad4. There are 815 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 24 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.966C>T | p.Ser322Ser | synonymous_variant | 8/25 | ENST00000269228.10 | NP_000262.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.966C>T | p.Ser322Ser | synonymous_variant | 8/25 | 1 | NM_000271.5 | ENSP00000269228.4 | ||
NPC1 | ENST00000591051.1 | c.246C>T | p.Ser82Ser | synonymous_variant | 3/18 | 2 | ENSP00000467636.1 | |||
NPC1 | ENST00000540608.5 | n.880C>T | non_coding_transcript_exon_variant | 6/16 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0113 AC: 1723AN: 152172Hom.: 24 Cov.: 32
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GnomAD3 exomes AF: 0.00376 AC: 939AN: 249884Hom.: 11 AF XY: 0.00326 AC XY: 441AN XY: 135282
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GnomAD4 exome AF: 0.00156 AC: 2282AN: 1461778Hom.: 43 Cov.: 32 AF XY: 0.00163 AC XY: 1188AN XY: 727190
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GnomAD4 genome AF: 0.0114 AC: 1732AN: 152290Hom.: 24 Cov.: 32 AF XY: 0.0109 AC XY: 815AN XY: 74474
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ClinVar
Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
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 | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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. - |
not specified Benign:1
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
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DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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