chr10-72368386-A-C

Variant names:

• chr10-72368386-A-C
• rs149949660
• NM_001195518.2:c.1271-31T>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001195518.2(MICU1):​c.1271-31T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,601,568 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (30 hom.)
• Consequence: MICU1 NM_001195518.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.53
• Publications: 0 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):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• proximal myopathy with extrapyramidal signs

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 10-72368386-A-C is Benign according to our data. Variant chr10-72368386-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1210618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00106 (162/152342) while in subpopulation SAS AF = 0.0135 (65/4828). AF 95% confidence interval is 0.0108. There are 3 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MICU1	NM_001195518.2	MANE Select	c.1271-31T>G		intron	N/A	NP_001182447.1	Q9BPX6-1
	MICU1	NM_001441218.1		c.1502-31T>G		intron	N/A	NP_001428147.1
	MICU1	NM_001441219.1		c.1439-31T>G		intron	N/A	NP_001428148.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MICU1	ENST00000361114.10	TSL:1 MANE Select	c.1271-31T>G		intron	N/A	ENSP00000354415.5	Q9BPX6-1
	MICU1	ENST00000964210.1		c.1502-31T>G		intron	N/A	ENSP00000634269.1
	MICU1	ENST00000897977.1		c.1439-31T>G		intron	N/A	ENSP00000568036.1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152224 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00276 AC: 680 AN: 246414 AF XY: 0.00321

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000581

Gnomad ASJ exome AF: 0.00629

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0000484

Gnomad NFE exome AF: 0.000917

Gnomad OTH exome AF: 0.00349

GnomAD4 exome AF: 0.00157 AC: 2277 AN: 1449226 Hom.: 30 Cov.: 31 AF XY: 0.00199 AC XY: 1426 AN XY: 718300

African (AFR) AF: 0.0000300 AC: 1 AN: 33304

American (AMR) AF: 0.000628 AC: 28 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.00580 AC: 151 AN: 26040

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39332

South Asian (SAS) AF: 0.0156 AC: 1344 AN: 86086

European-Finnish (FIN) AF: 0.0000575 AC: 3 AN: 52202

Middle Eastern (MID) AF: 0.00453 AC: 26 AN: 5738

European-Non Finnish (NFE) AF: 0.000534 AC: 588 AN: 1102070

Other (OTH) AF: 0.00224 AC: 134 AN: 59876

GnomAD4 genome AF: 0.00106 AC: 162 AN: 152342 Hom.: 3 Cov.: 31 AF XY: 0.00114 AC XY: 85 AN XY: 74500

African (AFR) AF: 0.0000481 AC: 2 AN: 41582

American (AMR) AF: 0.000653 AC: 10 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68030

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00151 Hom.: 0

Bravo AF: 0.000782

Asia WGS AF: 0.00462 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	17
DANN	Benign	0.59
PhyloP100		2.5
BranchPoint Hunter		7.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149949660; hg19: chr10-74128144;