11-66866178-TCCGC-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_001040716.2(PC):c.1185+5_1185+8delGCGG variant causes a splice region, 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
Consequence
NM_001040716.2 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PC | NM_001040716.2 | c.1185+5_1185+8delGCGG | splice_region_variant, intron_variant | Intron 11 of 22 | ENST00000393960.7 | NP_001035806.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000263 AC: 40AN: 151892Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000259 AC: 63AN: 243580Hom.: 0 AF XY: 0.000279 AC XY: 37AN XY: 132488
GnomAD4 exome AF: 0.000343 AC: 499AN: 1453230Hom.: 1 AF XY: 0.000349 AC XY: 252AN XY: 722878
GnomAD4 genome AF: 0.000263 AC: 40AN: 151892Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21AN XY: 74184
ClinVar
Submissions by phenotype
Pyruvate carboxylase deficiency Uncertain:2
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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. -
not provided Uncertain:2
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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
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
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at