rs753706965
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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.Arg193Ter) 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
Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000087 ( 2 hom. )
Consequence
PCK2
NM_004563.4 stop_gained
NM_004563.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.63
Genes affected
PCK2 (HGNC:8725): (phosphoenolpyruvate carboxykinase 2, mitochondrial) This gene encodes a mitochondrial enzyme that catalyzes the conversion of oxaloacetate to phosphoenolpyruvate in the presence of guanosine triphosphate (GTP). A cytosolic form of this protein is encoded by a different gene and is the key enzyme of gluconeogenesis in the liver. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2014]
NRL (HGNC:8002): (neural retina leucine zipper) This gene encodes a basic motif-leucine zipper transcription factor of the Maf subfamily. The encoded protein is conserved among vertebrates and is a critical intrinsic regulator of photoceptor development and function. Mutations in this gene have been associated with retinitis pigmentosa and retinal degenerative diseases. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
BS2
?
High AC in GnomAd4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCK2 | NM_004563.4 | c.577C>T | p.Arg193Ter | stop_gained | 4/10 | ENST00000216780.9 | |
NRL | NM_001354768.3 | c.-27-15716G>A | intron_variant | ENST00000561028.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCK2 | ENST00000216780.9 | c.577C>T | p.Arg193Ter | stop_gained | 4/10 | 1 | NM_004563.4 | P1 | |
NRL | ENST00000561028.6 | c.-27-15716G>A | intron_variant | 2 | NM_001354768.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152192Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000876 AC: 22AN: 251200Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135776
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GnomAD4 exome AF: 0.0000869 AC: 127AN: 1461756Hom.: 2 Cov.: 33 AF XY: 0.0000839 AC XY: 61AN XY: 727186
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 09, 2018 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 28, 2022 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 451808). This variant has not been reported in the literature in individuals affected with PCK2-related conditions. This variant is present in population databases (rs753706965, gnomAD 0.01%). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 09, 2018 | - - |
Phosphoenolpyruvate carboxykinase deficiency, mitochondrial Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 03, 2017 | - - |
Retinitis pigmentosa 27 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;A;A;A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 24
Find out detailed SpliceAI scores and Pangolin per-transcript scores at