10-72692219-C-T

Variant names:

• chr10-72692219-C-T
• rs758278264
• NM_138357.3:c.68C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_138357.3(MCU):​c.68C>T​(p.Ala23Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000457 in 1,094,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A23T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: MCU NM_138357.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.646
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10597879).
• BS2: High AC in GnomAdExome4 at 5 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCU	NM_138357.3	MANE Select	c.68C>T	p.Ala23Val	missense	Exon 1 of 8	NP_612366.1	Q8NE86-1
	MCU	NM_001270679.2		c.68C>T	p.Ala23Val	missense	Exon 1 of 8	NP_001257608.1	Q8NE86-2
	MCU	NR_073062.2		n.77C>T		non_coding_transcript_exon	Exon 1 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCU	ENST00000373053.8	TSL:1 MANE Select	c.68C>T	p.Ala23Val	missense	Exon 1 of 8	ENSP00000362144.3	Q8NE86-1
	MCU	ENST00000357157.10	TSL:1	c.68C>T	p.Ala23Val	missense	Exon 1 of 8	ENSP00000349680.6	Q8NE86-2
	MCU	ENST00000604372.5	TSL:1	n.68C>T		non_coding_transcript_exon	Exon 1 of 8	ENSP00000474820.1	S4R3W8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000457 AC: 5 AN: 1094958 Hom.: 0 Cov.: 30 AF XY: 0.00000193 AC XY: 1 AN XY: 517862

African (AFR) AF: 0.00 AC: 0 AN: 23020

American (AMR) AF: 0.00 AC: 0 AN: 9100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14374

East Asian (EAS) AF: 0.00 AC: 0 AN: 26710

South Asian (SAS) AF: 0.00 AC: 0 AN: 19904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3064

European-Non Finnish (NFE) AF: 0.00000434 AC: 4 AN: 921566

Other (OTH) AF: 0.0000228 AC: 1 AN: 43788

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.65
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.091
Sift	Benign	0.33	T
Sift4G	Benign	0.36	T
Polyphen		0.049	B
Vest4		0.30
MVP		0.13
MPC		0.61
ClinPred		0.32	T
GERP RS		3.4
PromoterAI		0.061	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.11
gMVP		0.27
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs758278264; hg19: chr10-74451977;