rs749124658

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001195518.2(MICU1):c.40delG(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

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 1.07

Publications

1 publications found

Variant links:

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]

MICU1 Gene-Disease associations (from GenCC):

proximal myopathy with extrapyramidal signs
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P

MICU1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 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 24 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 431146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195518.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MICU1	NM_001195518.2	MANE Select	c.40delG	p.Ala14LeufsTer20	frameshift	Exon 2 of 12	NP_001182447.1
MICU1	NM_001441218.1		c.40delG	p.Ala14LeufsTer20	frameshift	Exon 2 of 13	NP_001428147.1
MICU1	NM_001441219.1		c.40delG	p.Ala14LeufsTer20	frameshift	Exon 2 of 13	NP_001428148.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MICU1	ENST00000361114.10	TSL:1 MANE Select	c.40delG	p.Ala14LeufsTer20	frameshift	Exon 2 of 12	ENSP00000354415.5
MICU1	ENST00000642044.1		c.40delG	p.Ala14LeufsTer20	frameshift	Exon 2 of 14	ENSP00000493232.1
MICU1	ENST00000635239.1	TSL:5	c.40delG	p.Ala14LeufsTer20	frameshift	Exon 2 of 13	ENSP00000489563.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000163

AC:

AN:

246022

AF XY:

0.00000750

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000359

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000678

AC:

AN:

1460336

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

726346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.00

AC:

AN:

44436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

85942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000873

AC:

AN:

1111322

Other (OTH)

AF:

0.0000331

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Proximal myopathy with extrapyramidal signs

Pathogenic:3

Jan 13, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 06, 2017

Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Intellectual disability, mild; pyramidal syndrome; dystonia; myoclonus; sensitivo-motor axonal neuropathy; hypotonia; intestinal malrotation

Jul 29, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

not provided

Pathogenic:2

Jan 31, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33969448, 28708303)

Jul 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Inborn genetic diseases

Pathogenic:1

Jun 27, 2017

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Neurodevelopmental disorder

Pathogenic:1

Mar 22, 2022

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Mutation Taster

=4/196

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over