21-46412065-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006031.6(PCNT):c.5992C>T(p.Gln1998Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000467 in 1,606,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_006031.6 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCNT | NM_006031.6 | c.5992C>T | p.Gln1998Ter | stop_gained, splice_region_variant | 28/47 | ENST00000359568.10 | |
PCNT | NM_001315529.2 | c.5638C>T | p.Gln1880Ter | stop_gained, splice_region_variant | 28/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCNT | ENST00000359568.10 | c.5992C>T | p.Gln1998Ter | stop_gained, splice_region_variant | 28/47 | 1 | NM_006031.6 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000128 AC: 3AN: 234872Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 128838
GnomAD4 exome AF: 0.0000488 AC: 71AN: 1454044Hom.: 0 Cov.: 34 AF XY: 0.0000511 AC XY: 37AN XY: 723622
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2023 | PCNT: PVS1, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Gln1998*) in the PCNT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCNT are known to be pathogenic (PMID: 18174396, 22821869). This variant is present in population databases (rs757577162, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with microcephalic osteodysplastic primordial dwarfism type II (PMID: 18174396). ClinVar contains an entry for this variant (Variation ID: 436268). For these reasons, this variant has been classified as Pathogenic. - |
PCNT-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 09, 2024 | The PCNT c.5992C>T variant is predicted to result in premature protein termination (p.Gln1998*). This variant, with a second PCNT variant, has been reported in individuals with microcephalic osteodysplastic primordial dwarfism type 2 (Table S2, Rauch et al. 2008. PubMed ID: 18174396; Table S1, Bober et al. 2012. PubMed ID: 22821869). This variant is reported in 0.0057% of alleles in individuals of European (Finnish) descent in gnomAD. Nonsense variants in PCNT are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Microcephalic osteodysplastic primordial dwarfism type II Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 30, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at