chr14-74480292-T-G
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_006432.5(NPC2):c.442-4A>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,612,074 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_006432.5 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC2 | NM_006432.5 | c.442-4A>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000555619.6 | |||
NPC2 | NM_001363688.1 | c.*326A>C | 3_prime_UTR_variant | 4/4 | |||
NPC2 | NM_001375440.1 | c.364-4A>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC2 | ENST00000555619.6 | c.442-4A>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_006432.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00769 AC: 1170AN: 152168Hom.: 19 Cov.: 32
GnomAD3 exomes AF: 0.00621 AC: 1547AN: 249162Hom.: 43 AF XY: 0.00741 AC XY: 1000AN XY: 134882
GnomAD4 exome AF: 0.00285 AC: 4158AN: 1459788Hom.: 100 Cov.: 30 AF XY: 0.00374 AC XY: 2719AN XY: 726380
GnomAD4 genome ? AF: 0.00767 AC: 1168AN: 152286Hom.: 19 Cov.: 32 AF XY: 0.00788 AC XY: 587AN XY: 74464
ClinVar
Submissions by phenotype
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 21, 2017 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 12, 2021 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 21, 2014 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Niemann-Pick disease, type C2 Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Niemann-Pick disease, type C1 Benign:1
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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at