rs200185747
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000532.5(PCCB):c.49C>A(p.Leu17Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 1,589,370 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L17L) has been classified as Likely benign.
Frequency
Consequence
NM_000532.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCCB | NM_000532.5 | c.49C>A | p.Leu17Met | missense_variant | 1/15 | ENST00000251654.9 | |
PCCB | NM_001178014.2 | c.49C>A | p.Leu17Met | missense_variant | 1/16 | ||
PCCB | XM_011512873.2 | c.49C>A | p.Leu17Met | missense_variant | 1/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCCB | ENST00000251654.9 | c.49C>A | p.Leu17Met | missense_variant | 1/15 | 1 | NM_000532.5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00159 AC: 242AN: 152270Hom.: 2 Cov.: 33
GnomAD3 exomes AF: 0.00153 AC: 313AN: 204210Hom.: 0 AF XY: 0.00151 AC XY: 168AN XY: 111604
GnomAD4 exome AF: 0.00250 AC: 3598AN: 1436982Hom.: 3 Cov.: 31 AF XY: 0.00236 AC XY: 1684AN XY: 712736
GnomAD4 genome ? AF: 0.00159 AC: 242AN: 152388Hom.: 2 Cov.: 33 AF XY: 0.00138 AC XY: 103AN XY: 74520
ClinVar
Submissions by phenotype
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 26, 2020 | This variant is associated with the following publications: (PMID: 12757933, 10447268, 27896094) - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Dec 02, 2016 | - - |
Propionic acidemia Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 16, 2020 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 25, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 24, 2022 | Variant summary: PCCB c.49C>A (p.Leu17Met) results in a conservative amino acid change located in the mitochondrial leader sequence (Chloupkova_2002) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 204310 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCCB causing Propionic Acidemia phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.49C>A has been reported in the literature in individuals affected with Propionic Acidemia (Muro_1999, Kruszka_2014). These reports do not provide unequivocal conclusions about association of the variant with Propionic Acidemia. At least one co-occurrence with another pathogenic variant has been reported (PCCB c.790dupG, p.Asp264Glyfs*3, Muro_1999), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely benign (n=4) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
PCCB-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 18, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at