Genetic Variant MCU:p.Arg41Leu (chr10-72692273-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_138357.3(MCU):c.122G>T(p.Arg41Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000326 in 1,227,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

MCU
NM_138357.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.35

Publications

0 publications found

Variant links:

Genes affected

MCU (HGNC:23526): (mitochondrial calcium uniporter) Enables calcium channel activity; identical protein binding activity; and uniporter activity. Involved in several processes, including positive regulation of mitochondrial calcium ion concentration; positive regulation of mitochondrial fission; and positive regulation of neutrophil chemotaxis. Acts upstream of or within calcium import into the mitochondrion. Located in mitochondrial inner membrane. Is integral component of mitochondrial inner membrane. Part of uniplex complex. [provided by Alliance of Genome Resources, Apr 2022]

MCU links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24851942).

BS2

High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138357.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCU	NM_138357.3	MANE Select	c.122G>T	p.Arg41Leu	missense	Exon 1 of 8	NP_612366.1	Q8NE86-1
MCU	NM_001270679.2		c.122G>T	p.Arg41Leu	missense	Exon 1 of 8	NP_001257608.1	Q8NE86-2
MCU	NR_073062.2		n.131G>T		non_coding_transcript_exon	Exon 1 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCU	ENST00000373053.8	TSL:1 MANE Select	c.122G>T	p.Arg41Leu	missense	Exon 1 of 8	ENSP00000362144.3	Q8NE86-1
MCU	ENST00000357157.10	TSL:1	c.122G>T	p.Arg41Leu	missense	Exon 1 of 8	ENSP00000349680.6	Q8NE86-2
MCU	ENST00000604372.5	TSL:1	n.122G>T		non_coding_transcript_exon	Exon 1 of 8	ENSP00000474820.1	S4R3W8

Frequencies

GnomAD3 genomes

AF:

0.0000396

AC:

AN:

151638

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000737

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000316

AC:

AN:

1076336

Hom.:

Cov.:

AF XY:

0.0000354

AC XY:

AN XY:

508442

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22574

American (AMR)

AF:

0.00

AC:

AN:

8166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13972

East Asian (EAS)

AF:

0.00

AC:

AN:

26030

South Asian (SAS)

AF:

0.00

AC:

AN:

19448

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24760

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2886

European-Non Finnish (NFE)

AF:

0.0000361

AC:

AN:

915362

Other (OTH)

AF:

0.0000232

AC:

AN:

43138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.0000396

AC:

AN:

151638

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74078

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41322

American (AMR)

AF:

0.00

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000737

AC:

AN:

67848

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.042

Eigen

Benign

0.068

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.73

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.25

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

PhyloP100

5.3

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.2

REVEL

Benign

0.051

Sift

Benign

0.80

Sift4G

Benign

0.28

Polyphen

0.25

Vest4

0.62

MutPred

0.32

Gain of sheet (P = 0.0266)

MVP

0.16

MPC

0.77

ClinPred

0.56

GERP RS

4.4

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.22

gMVP

0.35

Mutation Taster

=67/33

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over