NM_001040716.2:c.633+2T>C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001040716.2(PC):c.633+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000066 in 151,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001040716.2 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PC | NM_001040716.2 | c.633+2T>C | splice_donor_variant, intron_variant | Intron 7 of 22 | ENST00000393960.7 | NP_001035806.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000660 AC: 1AN: 151490Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250788Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135586
GnomAD4 exome Cov.: 33
GnomAD4 genome AF: 0.00000660 AC: 1AN: 151490Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73958
ClinVar
Submissions by phenotype
Pyruvate carboxylase deficiency Pathogenic:4
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In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 551488). This variant has not been reported in the literature in individuals affected with PC-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 6 of the PC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PC are known to be pathogenic (PMID: 12112657, 19306334). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at