NM_004563.4:c.68C>G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_StrongBS2
The NM_004563.4(PCK2):āc.68C>Gā(p.Ser23*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,613,536 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004563.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PCK2 | NM_004563.4 | c.68C>G | p.Ser23* | stop_gained | Exon 2 of 10 | ENST00000216780.9 | NP_004554.3 | |
NRL | NM_001354768.3 | c.-27-14055G>C | intron_variant | Intron 1 of 2 | ENST00000561028.6 | NP_001341697.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00202 AC: 308AN: 152174Hom.: 2 Cov.: 30
GnomAD3 exomes AF: 0.00188 AC: 472AN: 250952Hom.: 1 AF XY: 0.00179 AC XY: 243AN XY: 135654
GnomAD4 exome AF: 0.00310 AC: 4526AN: 1461244Hom.: 8 Cov.: 31 AF XY: 0.00303 AC XY: 2203AN XY: 726976
GnomAD4 genome AF: 0.00202 AC: 308AN: 152292Hom.: 2 Cov.: 30 AF XY: 0.00180 AC XY: 134AN XY: 74464
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:4Benign:1
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Identified in a patient with ataxia and weakness exacerbated by illness who also harbors an an additional missense variant in the PCK2 gene (PMID: 36845668); Reported as a de novo variant in a patient from the Deciphering Developmental Disorders cohort who also harbors additional de novo variants in a large cohort of individuals with cardiovascular disease traits (PMID: 31345219, 31785789); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868); This variant is associated with the following publications: (PMID: 31345219, 36845668, 31785789) -
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not specified Uncertain:1
The p.Ser23X variant in PCK2 has not been previously reported in individuals wit h PEPCK deficiency, but has been identified in 0.5% (61/11556) of Latino chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs61752842) including two homozygote individuals. This nonsense variant le ads to a premature termination codon at position 23, which is predicted to lead to a truncated or absent protein. However, a role for PCK2 loss of function vari ants in disease has not been established. In summary, while the clinical signifi cance of the p.Ser23X variant is uncertain, the frequency data in ExAC suggest a more likely benign role. -
Phosphoenolpyruvate carboxykinase deficiency, mitochondrial Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at