rs753706965
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PVS1BS2_Supporting
The NM_004563.4(PCK2):c.577C>T(p.Arg193*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000843 in 1,614,066 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004563.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PCK2 | NM_004563.4 | c.577C>T | p.Arg193* | stop_gained | Exon 4 of 10 | ENST00000216780.9 | NP_004554.3 | |
NRL | NM_001354768.3 | c.-27-15716G>A | intron_variant | Intron 1 of 2 | ENST00000561028.6 | NP_001341697.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000876 AC: 22AN: 251200Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135776
GnomAD4 exome AF: 0.0000869 AC: 127AN: 1461756Hom.: 2 Cov.: 33 AF XY: 0.0000839 AC XY: 61AN XY: 727186
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152310Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74478
ClinVar
Submissions by phenotype
not provided Uncertain:3
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The R193X variant in the PCK2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R193X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret R193X as a variant of uncertain significance. -
This sequence change creates a premature translational stop signal (p.Arg193*) in the PCK2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in PCK2 cause disease. This variant is present in population databases (rs753706965, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PCK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 451808). 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. -
Phosphoenolpyruvate carboxykinase deficiency, mitochondrial Pathogenic:1
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Retinitis pigmentosa 27 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at