chr14-74484420-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_006432.5(NPC2):c.358C>A(p.Pro120Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,850 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P120S) has been classified as Pathogenic.
Frequency
Consequence
NM_006432.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC2 | NM_006432.5 | c.358C>A | p.Pro120Thr | missense_variant | 3/5 | ENST00000555619.6 | |
NPC2 | NM_001363688.1 | c.358C>A | p.Pro120Thr | missense_variant | 3/4 | ||
NPC2 | NM_001375440.1 | c.358C>A | p.Pro120Thr | missense_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC2 | ENST00000555619.6 | c.358C>A | p.Pro120Thr | missense_variant | 3/5 | 1 | NM_006432.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461850Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727228
GnomAD4 genome ? Cov.: 30
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.358C>A (p.Pro120Thr) in NPC2 gene has been reported in homozygous state in individuals affected with Niemann-Pick disease type C (Parihar J. et al., 2021). This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Proline at position 120 is changed to a Threonine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. For these reasons, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at