Genetic Variant MCUB:c.*1043C>T (chr4-109688635-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_017918.5(MCUB):c.*1043C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 151,990 control chromosomes in the GnomAD database, including 35,178 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.68 ( 35178 hom., cov: 33)

Failed GnomAD Quality Control

Consequence

MCUB
NM_017918.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.415

Publications

6 publications found

Variant links:

Genes affected

MCUB (HGNC:26076): (mitochondrial calcium uniporter dominant negative subunit beta) Predicted to enable calcium channel inhibitor activity. Predicted to be involved in calcium import into the mitochondrion and mitochondrial calcium ion homeostasis. Located in mitochondrion and nucleoplasm. Is integral component of mitochondrial inner membrane. Part of uniplex complex. [provided by Alliance of Genome Resources, Apr 2022]

MCUB links:

CASP6 (HGNC:1507): (caspase 6) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family of enzymes. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic acid residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein is processed by caspases 7, 8 and 10, and is thought to function as a downstream enzyme in the caspase activation cascade. Alternative splicing of this gene results in multiple transcript variants that encode different isoforms. [provided by RefSeq, Oct 2015]

CASP6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017918.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MCUB	NM_017918.5	MANE Select	c.*1043C>T	3_prime_UTR	Exon 8 of 8	NP_060388.2
CASP6	NM_001226.4	MANE Select	c.*695G>A	3_prime_UTR	Exon 7 of 7	NP_001217.2
CASP6	NM_032992.3		c.*695G>A	3_prime_UTR	Exon 4 of 4	NP_116787.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MCUB	ENST00000394650.7	TSL:1 MANE Select	c.*1043C>T	3_prime_UTR	Exon 8 of 8	ENSP00000378145.4
CASP6	ENST00000265164.7	TSL:1 MANE Select	c.*695G>A	3_prime_UTR	Exon 7 of 7	ENSP00000265164.2
CASP6	ENST00000352981.7	TSL:1	c.*695G>A	3_prime_UTR	Exon 4 of 4	ENSP00000285333.3

Frequencies

GnomAD3 genomes

AF:

0.677

AC:

102775

AN:

151874

Hom.:

35136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.764

Gnomad AMI

AF:

0.688

Gnomad AMR

AF:

0.616

Gnomad ASJ

AF:

0.595

Gnomad EAS

AF:

0.485

Gnomad SAS

AF:

0.679

Gnomad FIN

AF:

0.643

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.662

Gnomad OTH

AF:

0.659

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.677

AC:

102871

AN:

151990

Hom.:

35178

Cov.:

AF XY:

0.672

AC XY:

49905

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.764

AC:

31677

AN:

41470

American (AMR)

AF:

0.616

AC:

9421

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.595

AC:

2067

AN:

3472

East Asian (EAS)

AF:

0.486

AC:

2509

AN:

5158

South Asian (SAS)

AF:

0.681

AC:

3280

AN:

4814

European-Finnish (FIN)

AF:

0.643

AC:

6769

AN:

10534

Middle Eastern (MID)

AF:

0.626

AC:

184

AN:

294

European-Non Finnish (NFE)

AF:

0.662

AC:

44949

AN:

67942

Other (OTH)

AF:

0.658

AC:

1389

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1709

3418

5126

6835

8544

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

816

1632

2448

3264

4080

<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:

0.668

Hom.:

13056

Bravo

AF:

0.677

Asia WGS

AF:

0.616

AC:

2125

AN:

3452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.6

(source)

DANN

Benign

0.68

PhyloP100

-0.41

Mutation Taster

=100/0

polymorphism (auto)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over