rs772395858
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_020166.5(MCCC1):c.640-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_020166.5 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCCC1 | NM_020166.5 | c.640-2A>G | splice_acceptor_variant | ENST00000265594.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCCC1 | ENST00000265594.9 | c.640-2A>G | splice_acceptor_variant | 1 | NM_020166.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251430Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135882
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 727240
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
3-methylcrotonyl-CoA carboxylase 1 deficiency Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 09, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change affects an acceptor splice site in intron 6 of the MCCC1 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 MCCC1 are known to be pathogenic (PMID: 11181649, 15359379, 22642865). This variant is present in population databases (rs772395858, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 27601257; Invitae). ClinVar contains an entry for this variant (Variation ID: 198578). 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 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 27, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Methylcrotonyl-CoA carboxylase deficiency Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 22, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at