rs749124658
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001195518.2(MICU1):c.40del(p.Ala14LeufsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000664 in 1,612,430 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000068 ( 0 hom. )
Consequence
MICU1
NM_001195518.2 frameshift
NM_001195518.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.07
Genes affected
MICU1 (HGNC:1530): (mitochondrial calcium uptake 1) This gene encodes an essential regulator of mitochondrial Ca2+ uptake under basal conditions. The encoded protein interacts with the mitochondrial calcium uniporter, a mitochondrial inner membrane Ca2+ channel, and is essential in preventing mitochondrial Ca2+ overload, which can cause excessive production of reactive oxygen species and cell stress. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2013]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 19 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 10-72566753-GC-G is Pathogenic according to our data. Variant chr10-72566753-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MICU1 | NM_001195518.2 | c.40del | p.Ala14LeufsTer20 | frameshift_variant | 2/12 | ENST00000361114.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MICU1 | ENST00000361114.10 | c.40del | p.Ala14LeufsTer20 | frameshift_variant | 2/12 | 1 | NM_001195518.2 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152094Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
8
AN:
152094
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000163 AC: 4AN: 246022Hom.: 0 AF XY: 0.00000750 AC XY: 1AN XY: 133388
GnomAD3 exomes
AF:
AC:
4
AN:
246022
Hom.:
AF XY:
AC XY:
1
AN XY:
133388
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000678 AC: 99AN: 1460336Hom.: 0 Cov.: 31 AF XY: 0.0000564 AC XY: 41AN XY: 726346
GnomAD4 exome
AF:
AC:
99
AN:
1460336
Hom.:
Cov.:
31
AF XY:
AC XY:
41
AN XY:
726346
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74282
GnomAD4 genome
?
AF:
AC:
8
AN:
152094
Hom.:
Cov.:
32
AF XY:
AC XY:
4
AN XY:
74282
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Proximal myopathy with extrapyramidal signs Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 29, 2022 | Variant summary: CBARA1 (MICU1) c.40delG (p.Ala14LeufsX20) 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, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar (e.g. c.355C>T (p.Arg119*), c.547C>T (p.Gln183*))The variant allele was found at a frequency of 2.5e-05 in 277426 control chromosomes (gnomAD). c.40delG has been reported in the literature in at least one compound heterozygous individual affected with Myopathy With Extrapyramidal Signs (e.g. Cherot_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic (n=1) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris | Jan 06, 2017 | Intellectual disability, mild; pyramidal syndrome; dystonia; myoclonus; sensitivo-motor axonal neuropathy; hypotonia; intestinal malrotation - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 13, 2023 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 27, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change creates a premature translational stop signal (p.Ala14Leufs*20) in the MICU1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MICU1 are known to be pathogenic (PMID: 24336167). This variant is present in population databases (rs749124658, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with a neurodevelopmental disorder (PMID: 28708303). ClinVar contains an entry for this variant (Variation ID: 431146). For these reasons, this variant has been classified as Pathogenic. - |
Neurodevelopmental disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Mar 22, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at