chr3-183015536-CT-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_020166.5(MCCC1):c.2079del(p.Val694Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T693T) has been classified as Likely benign.
Frequency
Consequence
NM_020166.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCCC1 | NM_020166.5 | c.2079del | p.Val694Ter | frameshift_variant | 19/19 | ENST00000265594.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCCC1 | ENST00000265594.9 | c.2079del | p.Val694Ter | frameshift_variant | 19/19 | 1 | NM_020166.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249234Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 134890
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461826Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727216
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
3-methylcrotonyl-CoA carboxylase 1 deficiency Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 16, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 17, 2023 | ClinVar contains an entry for this variant (Variation ID: 1934). This premature translational stop signal has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 11406611, 22642865). This variant is present in population databases (rs119103217, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Val694*) in the MCCC1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the MCCC1 protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the MCCC1 protein. Other variant(s) that disrupt this region (p.Val697Serfs*19) have been observed in individuals with MCCC1-related conditions (PMID: 16010683, 22642865). This suggests that this may be a clinically significant region of the protein. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 17, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 05, 2022 | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 32 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD (Stenson et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34426522, 32778825, 22642865, 11406611) - |
Methylcrotonyl-CoA carboxylase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
MCCC1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 22, 2022 | The MCCC1 c.2079delA variant is predicted to result in premature protein termination (p.Val694*). This variant has been reported in individuals with autosomal recessive 3-methylcrotonyl-CoA carboxylase deficiency (Holzinger et al 2001. PubMed ID: 11406611; Grünert et al 2012. PubMed ID: 22642865). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-182733324-CT-C). Nonsense variants in MCCC1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at