rs758278264

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr10-72692219-C-G
• chr10-72692219-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138357.3(MCU):​c.68C>G​(p.Ala23Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000016 in 1,246,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. A23V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: MCU NM_138357.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12255302).

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>G	p.Ala23Gly	missense	Exon 1 of 8	NP_612366.1	Q8NE86-1
	MCU	NM_001270679.2		c.68C>G	p.Ala23Gly	missense	Exon 1 of 8	NP_001257608.1	Q8NE86-2
	MCU	NR_073062.2		n.77C>G		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>G	p.Ala23Gly	missense	Exon 1 of 8	ENSP00000362144.3	Q8NE86-1
	MCU	ENST00000357157.10	TSL:1	c.68C>G	p.Ala23Gly	missense	Exon 1 of 8	ENSP00000349680.6	Q8NE86-2
	MCU	ENST00000604372.5	TSL:1	n.68C>G		non_coding_transcript_exon	Exon 1 of 8	ENSP00000474820.1	S4R3W8

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151598 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.13e-7 AC: 1 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: 0.0000374 AC: 1 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: 0.00 AC: 0 AN: 921566

Other (OTH) AF: 0.00 AC: 0 AN: 43788

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151598 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74042

African (AFR) AF: 0.0000242 AC: 1 AN: 41300

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67792

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.65
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.087
Sift	Benign	0.55	T
Sift4G	Benign	0.37	T
Polyphen		0.092	B
Vest4		0.33
MutPred		0.28		Gain of relative solvent accessibility (P = 0.09)
MVP		0.42
MPC		0.62
ClinPred		0.22	T
GERP RS		3.4
PromoterAI		0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.12
gMVP		0.25
Mutation Taster		=83/17	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;