rs752386083
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The ENST00000269228.10(NPC1):c.2234C>A(p.Ala745Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,445,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A745A) has been classified as Likely benign.
Frequency
Consequence
ENST00000269228.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.2234C>A | p.Ala745Glu | missense_variant | 14/25 | ENST00000269228.10 | NP_000262.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.2234C>A | p.Ala745Glu | missense_variant | 14/25 | 1 | NM_000271.5 | ENSP00000269228 | P1 | |
NPC1 | ENST00000591051.1 | c.1313C>A | p.Ala438Glu | missense_variant | 7/18 | 2 | ENSP00000467636 | |||
NPC1 | ENST00000540608.5 | n.2148C>A | non_coding_transcript_exon_variant | 12/16 | 2 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251150Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135752
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1445220Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1AN XY: 720170
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 31, 2021 | This sequence change replaces alanine with glutamic acid at codon 745 of the NPC1 protein (p.Ala745Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is present in population databases (rs752386083, ExAC 0.002%). This missense change has been observed in individual(s) with Niemann-Pick type C (PMID: 12955717). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 02, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 13, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at