rs202049874
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000282.4(PCCA):c.231+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,606,098 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0028 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0027 ( 19 hom. )
Consequence
PCCA
NM_000282.4 intron
NM_000282.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.224
Genes affected
PCCA (HGNC:8653): (propionyl-CoA carboxylase subunit alpha) The protein encoded by this gene is the alpha subunit of the heterodimeric mitochondrial enzyme Propionyl-CoA carboxylase. PCCA encodes the biotin-binding region of this enzyme. Mutations in either PCCA or PCCB (encoding the beta subunit) lead to an enzyme deficiency resulting in propionic acidemia. 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 Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant 13-100111903-C-T is Benign according to our data. Variant chr13-100111903-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 310842.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1, Benign=2}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00275 (418/151918) while in subpopulation NFE AF= 0.00244 (166/67944). AF 95% confidence interval is 0.00214. There are 2 homozygotes in gnomad4. There are 261 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AR gene
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00275 AC: 418AN: 151802Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.00310 AC: 776AN: 250160Hom.: 6 AF XY: 0.00299 AC XY: 405AN XY: 135350
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GnomAD4 exome AF: 0.00271 AC: 3946AN: 1454180Hom.: 19 Cov.: 29 AF XY: 0.00266 AC XY: 1922AN XY: 723856
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GnomAD4 genome AF: 0.00275 AC: 418AN: 151918Hom.: 2 Cov.: 32 AF XY: 0.00352 AC XY: 261AN XY: 74250
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 16, 2020 | Variant summary: PCCA c.231+15C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0031 in 250160 control chromosomes in the gnomAD database, including 6 homozygotes. This frequency is somewhat close to the estimated maximal expected allele frequency for a pathogenic PCCA variant causing Propionic Acidemia (0.0031 vs 0.0034), suggesting this variant might represent a benign polymorphism. To our knowledge, no occurrence of c.231+15C>T in individuals affected with Propionic Acidemia and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=2) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 16, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Propionic acidemia Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 11, 2017 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at