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

Variant summary

Our verdict is Likely benign. Variant got -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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

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

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCU	NM_138357.3 link	c.122G>T	p.Arg41Leu	missense_variant	Exon 1 of 8	ENST00000373053.8	NP_612366.1	Q8NE86-1
MCU	NM_001270679.2 link	c.122G>T	p.Arg41Leu	missense_variant	Exon 1 of 8		NP_001257608.1	Q8NE86-2
MCU	NR_073062.2 link	n.131G>T		non_coding_transcript_exon_variant	Exon 1 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCU	ENST00000373053.8 link	c.122G>T	p.Arg41Leu	missense_variant	Exon 1 of 8	1	NM_138357.3	ENSP00000362144.3		Q8NE86-1

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000361

Gnomad4 OTH exome

AF:

0.0000232

GnomAD4 genome

AF:

0.0000396

AC:

AN:

151638

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74078

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000737

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.122G>T (p.R41L) alteration is located in exon 1 (coding exon 1) of the MCU gene. This alteration results from a G to T substitution at nucleotide position 122, causing the arginine (R) at amino acid position 41 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.042

T;.

Eigen

Benign

0.068

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.73

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.051

Sift

Benign

0.80

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.25

B;P

Vest4

0.62

MutPred

0.32

Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);

MVP

0.16

MPC

0.77

ClinPred

0.56

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.22

gMVP

0.35

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over