rs10509343

Variant names:

• chr10-72533826-A-T
• rs10509343
• NM_001195518.2:c.494-37T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001195518.2(MICU1):​c.494-37T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.639 in 1,409,988 control chromosomes in the GnomAD database, including 300,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31128 hom., cov: 32)
  • Exomes 𝑓: 0.64 (268972 hom.)
• Consequence: MICU1 NM_001195518.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.196
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-72533826-A-T is Benign according to our data. Variant chr10-72533826-A-T is described in ClinVar as [Benign]. Clinvar id is 1248259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MICU1	NM_001195518.2	c.494-37T>A		intron_variant	Intron 4 of 11	ENST00000361114.10	NP_001182447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MICU1	ENST00000361114.10	c.494-37T>A		intron_variant	Intron 4 of 11	1	NM_001195518.2	ENSP00000354415.5

Frequencies

GnomAD3 genomes AF: 0.625 AC: 94746 AN: 151496 Hom.: 31104 Cov.: 32

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.562

Gnomad EAS AF: 0.0427

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.662

Gnomad NFE AF: 0.672

Gnomad OTH AF: 0.620

GnomAD2 exomes AF: 0.562 AC: 96089 AN: 171082 AF XY: 0.565

Gnomad AFR exome AF: 0.724

Gnomad AMR exome AF: 0.459

Gnomad ASJ exome AF: 0.582

Gnomad EAS exome AF: 0.0326

Gnomad FIN exome AF: 0.522

Gnomad NFE exome AF: 0.683

Gnomad OTH exome AF: 0.598

GnomAD4 exome AF: 0.641 AC: 806504 AN: 1258374 Hom.: 268972 Cov.: 17 AF XY: 0.637 AC XY: 401496 AN XY: 629956

African (AFR) AF: 0.720 AC: 20452 AN: 28418

American (AMR) AF: 0.467 AC: 14852 AN: 31830

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 13410 AN: 23354

East Asian (EAS) AF: 0.0673 AC: 2538 AN: 37722

South Asian (SAS) AF: 0.477 AC: 34682 AN: 72704

European-Finnish (FIN) AF: 0.524 AC: 24705 AN: 47104

Middle Eastern (MID) AF: 0.677 AC: 3625 AN: 5354

European-Non Finnish (NFE) AF: 0.688 AC: 659456 AN: 958482

Other (OTH) AF: 0.614 AC: 32784 AN: 53406

GnomAD4 genome AF: 0.625 AC: 94812 AN: 151614 Hom.: 31128 Cov.: 32 AF XY: 0.607 AC XY: 44981 AN XY: 74080

African (AFR) AF: 0.719 AC: 29730 AN: 41336

American (AMR) AF: 0.526 AC: 8034 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 1949 AN: 3466

East Asian (EAS) AF: 0.0426 AC: 221 AN: 5184

South Asian (SAS) AF: 0.440 AC: 2122 AN: 4820

European-Finnish (FIN) AF: 0.491 AC: 5150 AN: 10486

Middle Eastern (MID) AF: 0.647 AC: 189 AN: 292

European-Non Finnish (NFE) AF: 0.672 AC: 45550 AN: 67760

Other (OTH) AF: 0.615 AC: 1296 AN: 2108

Alfa AF: 0.644 Hom.: 5920

Bravo AF: 0.630

Asia WGS AF: 0.268 AC: 933 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.43
DANN	Benign	0.78
PhyloP100		-0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10509343; hg19: chr10-74293584;