Variant 4-109660341-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017918.5(MCUB):c.322A>G(p.Lys108Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000289 in 1,454,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

MCUB
NM_017918.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.75

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:

MCUB (HGNC:):

MCUB links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06717187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCUB	NM_017918.5 linkuse as main transcript	c.322A>G	p.Lys108Glu	missense_variant	3/8	ENST00000394650.7	NP_060388.2	Q9NWR8
MCUB	XM_006714246.4 linkuse as main transcript	c.235A>G	p.Lys79Glu	missense_variant	3/8		XP_006714309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MCUB	ENST00000394650.7 linkuse as main transcript	c.322A>G	p.Lys108Glu	missense_variant	3/8	1	NM_017918.5	ENSP00000378145.4	Q9NWR8
MCUB	ENST00000472310.5 linkuse as main transcript	n.451A>G		non_coding_transcript_exon_variant	3/5	1
MCUB	ENST00000452915.3 linkuse as main transcript	n.417A>G		non_coding_transcript_exon_variant	4/6	5
MCUB	ENST00000515114.3 linkuse as main transcript	n.448A>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249772

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134976

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000289

AC:

AN:

1454658

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

724126

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:

0.0000289

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.322A>G (p.K108E) alteration is located in exon 3 (coding exon 3) of the MCUB gene. This alteration results from a A to G substitution at nucleotide position 322, causing the lysine (K) at amino acid position 108 to be replaced by a glutamic acid (E). 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

0.082

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.00065

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.51

M_CAP

Benign

0.0041

MetaRNN

Benign

0.067

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PrimateAI

Benign

0.31

PROVEAN

Benign

1.1

REVEL

Benign

0.029

Sift

Benign

0.56

Sift4G

Benign

0.30

Polyphen

0.0020

Vest4

0.078

MutPred

0.43

Loss of ubiquitination at K108 (P = 0.0116);

MVP

0.12

MPC

0.12

ClinPred

0.019

GERP RS

1.6

Varity_R

0.039

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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