rs202197769
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_002591.4(PCK1):āc.134T>Cā(p.Ile45Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Consequence
NM_002591.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCK1 | ENST00000319441.6 | c.134T>C | p.Ile45Thr | missense_variant | Exon 2 of 10 | 1 | NM_002591.4 | ENSP00000319814.4 | ||
PCK1 | ENST00000467047.1 | n.466T>C | non_coding_transcript_exon_variant | Exon 1 of 2 | 1 | |||||
PCK1 | ENST00000475833.1 | n.275T>C | non_coding_transcript_exon_variant | Exon 2 of 2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152166Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251348Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135840
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461618Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26AN XY: 727110
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152166Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74324
ClinVar
Submissions by phenotype
Phosphoenolpyruvate carboxykinase deficiency, cytosolic Pathogenic:1Uncertain:1
The PCK1 c.134T>C (p.Ile45Thr) variant has been reported in one study and in one sibling pair from non-consanguineous parents, both in a homozygous state (Adams et al. 2014). Both the unaffected parents were heterozygous for the variant. The p.Ile45Thr variant is reported at a frequency of 0.001726 in the Ashkenazi Jewish population of the Genome Aggregation Database. PEPCK-C (cytosolic) and PEPCK-M (mitochondrial) activity was measured in frozen liver from one of the patients, who was found to have less than or equal to 10% of immuno-reactive PEPCK-C levels. Expression of the p.Ile45Thr variant protein in E.coli revealed it to be expressed as an insoluble protein largely located in inclusion bodies. The half-life of the p.Ile45Thr variant protein was two hours as compared to the 24 hour half-life of the wild type protein. The p.Ile45Thr variant did not affect mRNA stability. Based on the limited evidence, the p.Ile45Thr variant is classified as a variant of unknown significance but suspicious for pathogenicity for phosphoenolpyruvate carboxykinase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at