rs769968548
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000532.5(PCCB):c.838dup(p.Leu280ProfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PCCB
NM_000532.5 frameshift
NM_000532.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.80
Genes affected
PCCB (HGNC:8654): (propionyl-CoA carboxylase subunit beta) The protein encoded by this gene is a subunit of the propionyl-CoA carboxylase (PCC) enzyme, which is involved in the catabolism of propionyl-CoA. PCC is a mitochondrial enzyme that probably acts as a dodecamer of six alpha subunits and six beta subunits. This gene encodes the beta subunit of PCC. Defects in this gene are a cause of propionic acidemia type II (PA-2). Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]
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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
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Very rare variant in population databases, with high coverage;
PP5
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Variant 3-136298022-G-GC is Pathogenic according to our data. Variant chr3-136298022-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCCB | NM_000532.5 | c.838dup | p.Leu280ProfsTer11 | frameshift_variant | 8/15 | ENST00000251654.9 | |
PCCB | NM_001178014.2 | c.898dup | p.Leu300ProfsTer11 | frameshift_variant | 9/16 | ||
PCCB | XM_011512873.2 | c.838dup | p.Leu280ProfsTer11 | frameshift_variant | 8/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCCB | ENST00000251654.9 | c.838dup | p.Leu280ProfsTer11 | frameshift_variant | 8/15 | 1 | NM_000532.5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 1AN: 152128Hom.: 0 Cov.: 32 FAILED QC
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461842Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727228
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74308
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Propionic acidemia Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 14, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 552435). This premature translational stop signal has been observed in individual(s) with propionic acidemia (PMID: 24863100). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs769968548, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Leu280Profs*11) in the PCCB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCCB are known to be pathogenic (PMID: 15464417). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 09, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 10, 2022 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at