rs748620956
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001040716.2(PC):c.1185+5_1185+8del variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,605,122 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00034 ( 1 hom. )
Consequence
PC
NM_001040716.2 splice_donor_5th_base, intron
NM_001040716.2 splice_donor_5th_base, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.25
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PC | NM_001040716.2 | c.1185+5_1185+8del | splice_donor_5th_base_variant, intron_variant | ENST00000393960.7 | NP_001035806.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PC | ENST00000393960.7 | c.1185+5_1185+8del | splice_donor_5th_base_variant, intron_variant | 5 | NM_001040716.2 | ENSP00000377532 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000263 AC: 40AN: 151892Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000259 AC: 63AN: 243580Hom.: 0 AF XY: 0.000279 AC XY: 37AN XY: 132488
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GnomAD4 exome AF: 0.000343 AC: 499AN: 1453230Hom.: 1 AF XY: 0.000349 AC XY: 252AN XY: 722878
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GnomAD4 genome AF: 0.000263 AC: 40AN: 151892Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21AN XY: 74184
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pyruvate carboxylase deficiency Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 08, 2022 | This sequence change falls in intron 10 of the PC gene. It does not directly change the encoded amino acid sequence of the PC protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs748620956, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PC-related conditions. ClinVar contains an entry for this variant (Variation ID: 426656). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Counsyl | Sep 05, 2017 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jun 02, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 30, 2024 | Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 08, 2024 | Variant summary: PC c.1185+5_1185+8delGCGG removes 4 nucleotides located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes a 5' splicing donor site, while one predicts the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00034 in 1,605,122 control chromosomes in the gnomAD database (v4.0 dataset), including 1 homozygote. This frequency is not higher than the estimated maximum expected for a pathogenic variant in PC causing Pyruvate Carboxylase Deficiency (0.00034 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1185+5_1185+8delGCGG in individuals affected with Pyruvate Carboxylase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 426656). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 28, 2021 | The c.1185+5_1185+8delGCGG alteration is located in Intron 10 (E) of the PC gene. This alteration consists of a deletion of 4 nucleotides between nucleotide positions c.11855 and c.11858 Intron 10 (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -38
DS_DL_spliceai
Position offset: 9
Find out detailed SpliceAI scores and Pangolin per-transcript scores at