10-72871440-G-T

Variant names:

• chr10-72871440-G-T
• rs760003771
• NM_138357.3:c.721G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_138357.3(MCU):​c.721G>T​(p.Ala241Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A241T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCU NM_138357.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.721G>T	p.Ala241Ser	missense	Exon 6 of 8	NP_612366.1	Q8NE86-1
	MCU	NM_001270679.2		c.658G>T	p.Ala220Ser	missense	Exon 6 of 8	NP_001257608.1	Q8NE86-2
	MCU	NM_001270680.3		c.574G>T	p.Ala192Ser	missense	Exon 6 of 8	NP_001257609.1	Q8NE86-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCU	ENST00000373053.8	TSL:1 MANE Select	c.721G>T	p.Ala241Ser	missense	Exon 6 of 8	ENSP00000362144.3	Q8NE86-1
	MCU	ENST00000357157.10	TSL:1	c.658G>T	p.Ala220Ser	missense	Exon 6 of 8	ENSP00000349680.6	Q8NE86-2
	MCU	ENST00000857904.1		c.721G>T	p.Ala241Ser	missense	Exon 6 of 9	ENSP00000527963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		10
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.029	D
Polyphen		0.98	D
Vest4		0.76
MutPred		0.67		Gain of MoRF binding (P = 0.1162)
MVP		0.35
MPC		1.4
ClinPred		0.93	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.94
Mutation Taster		=29/71	disease causing

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: rs760003771; hg19: chr10-74631198;