rs756355930
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001040716.2(PC):βc.2493_2494delβ(p.Phe832Ter) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000118 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 33)
Exomes π: 0.000012 ( 0 hom. )
Consequence
PC
NM_001040716.2 frameshift
NM_001040716.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.03
Genes affected
PC (HGNC:8636): (pyruvate carboxylase) This gene encodes pyruvate carboxylase, which requires biotin and ATP to catalyse the carboxylation of pyruvate to oxaloacetate. The active enzyme is a homotetramer arranged in a tetrahedron which is located exclusively in the mitochondrial matrix. Pyruvate carboxylase is involved in gluconeogenesis, lipogenesis, insulin secretion and synthesis of the neurotransmitter glutamate. Mutations in this gene have been associated with pyruvate carboxylase deficiency. Alternatively spliced transcript variants with different 5' UTRs, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-66850443-AAC-A is Pathogenic according to our data. Variant chr11-66850443-AAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 556347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PC | NM_001040716.2 | c.2493_2494del | p.Phe832Ter | frameshift_variant | 19/23 | ENST00000393960.7 | NP_001035806.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PC | ENST00000393960.7 | c.2493_2494del | p.Phe832Ter | frameshift_variant | 19/23 | 5 | NM_001040716.2 | ENSP00000377532 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152094Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251026Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135764
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461690Hom.: 0 AF XY: 0.0000110 AC XY: 8AN XY: 727148
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152094Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74294
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pyruvate carboxylase deficiency Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 25, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 05, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 29, 2023 | This sequence change creates a premature translational stop signal (p.Phe832*) in the PC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PC are known to be pathogenic (PMID: 12112657, 19306334). This variant is present in population databases (rs756355930, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with pyruvate carboxylase deficiency (PMID: 12112657, 18676167). This variant is also known as 2491-2492delGT. ClinVar contains an entry for this variant (Variation ID: 556347). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at