2-71110081-CT-CTT
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_032601.4(MCEE):c.419dupA(p.Lys141GlufsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000931 in 1,611,984 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_032601.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MCEE | ENST00000244217.6 | c.419dupA | p.Lys141GlufsTer7 | frameshift_variant | Exon 3 of 3 | 1 | NM_032601.4 | ENSP00000244217.5 | ||
MCEE | ENST00000413592.5 | c.125dupA | p.Lys43GlufsTer7 | frameshift_variant | Exon 2 of 2 | 2 | ENSP00000391140.1 | |||
MCEE | ENST00000462609.2 | n.365dupA | non_coding_transcript_exon_variant | Exon 5 of 5 | 3 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151896Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000959 AC: 14AN: 1460088Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9AN XY: 726388
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151896Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74190
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: MCEE c.419dupA (p.Lys141GlufsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. A truncating mutation located in close proximity to the current variant (p.Lys140Argfs*6) has been reported in HGMD in association with Parkinson disease, dementia, stroke and elevated levels of methylmalonic acid. While the current variant may not result in NMD, it alters several amino acids located in the Vicinal oxygen chelate (VOC) domain (Interpro). It is unclear what impact the variant will have on the function of this protein. The variant was absent in 250236 control chromosomes. To our knowledge, no occurrence of c.419dupA in individuals affected with Methylmalonic Acidemia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at