Genetic Variant MCU:p.Arg41His (chr10-72692273-G-A) – 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>A(p.Arg41His) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,076,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R41L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

MCU
NM_138357.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

Genome browser will be placed here

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=0.13405693).

BS2

High AC in GnomAdExome4 at 18 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>A	p.Arg41His	missense	Exon 1 of 8	NP_612366.1	Q8NE86-1
MCU	NM_001270679.2		c.122G>A	p.Arg41His	missense	Exon 1 of 8	NP_001257608.1	Q8NE86-2
MCU	NR_073062.2		n.131G>A		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>A	p.Arg41His	missense	Exon 1 of 8	ENSP00000362144.3	Q8NE86-1
MCU	ENST00000357157.10	TSL:1	c.122G>A	p.Arg41His	missense	Exon 1 of 8	ENSP00000349680.6	Q8NE86-2
MCU	ENST00000604372.5	TSL:1	n.122G>A		non_coding_transcript_exon	Exon 1 of 8	ENSP00000474820.1	S4R3W8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000167

AC:

AN:

1076336

Hom.:

Cov.:

AF XY:

0.0000177

AC XY:

AN XY:

508442

show subpopulations

African (AFR)

AF:

0.0000443

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:

0.0000514

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:

0.0000175

AC:

AN:

915362

Other (OTH)

AF:

0.00

AC:

AN:

43138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.038

Eigen

Benign

-0.13

Eigen_PC

Benign

0.027

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

5.3

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.3

REVEL

Benign

0.025

Sift

Benign

0.55

Sift4G

Uncertain

0.047

Polyphen

0.0020

Vest4

0.43

MutPred

0.20

Loss of MoRF binding (P = 0.0252)

MVP

0.16

MPC

0.76

ClinPred

0.70

GERP RS

4.4

PromoterAI

0.019

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.11

gMVP

0.29

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over