chr14-74480037-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_006432.5(NPC2):c.*237G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,476,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00024 ( 0 hom. )
Consequence
NPC2
NM_006432.5 3_prime_UTR
NM_006432.5 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.369
Genes affected
NPC2 (HGNC:14537): (NPC intracellular cholesterol transporter 2) This gene encodes a protein containing a lipid recognition domain. The encoded protein may function in regulating the transport of cholesterol through the late endosomal/lysosomal system. Mutations in this gene have been associated with Niemann-Pick disease, type C2 and frontal lobe atrophy. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000204 (31/152186) while in subpopulation AMR AF= 0.000981 (15/15294). AF 95% confidence interval is 0.000604. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC2 | NM_006432.5 | c.*237G>A | 3_prime_UTR_variant | 5/5 | ENST00000555619.6 | ||
SYNDIG1L | XM_017021600.2 | c.-5791G>A | 5_prime_UTR_variant | 1/4 | |||
NPC2 | NM_001363688.1 | c.*581G>A | 3_prime_UTR_variant | 4/4 | |||
NPC2 | NM_001375440.1 | c.*237G>A | 3_prime_UTR_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC2 | ENST00000555619.6 | c.*237G>A | 3_prime_UTR_variant | 5/5 | 1 | NM_006432.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000204 AC: 31AN: 152068Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000194 AC: 20AN: 103250Hom.: 0 AF XY: 0.000196 AC XY: 11AN XY: 56232
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GnomAD4 exome AF: 0.000236 AC: 313AN: 1324408Hom.: 0 Cov.: 31 AF XY: 0.000239 AC XY: 155AN XY: 649040
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Niemann-Pick disease, type C1 Uncertain:1
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
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