10-72692173-T-A

Variant names:

• chr10-72692173-T-A
• rs745829005
• NM_138357.3:c.22T>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_138357.3(MCU):​c.22T>A​(p.Ser8Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000441 in 1,134,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000044 (0 hom.)
• Consequence: MCU NM_138357.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

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

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32784915).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCU	NM_138357.3	c.22T>A	p.Ser8Thr	missense_variant	Exon 1 of 8	ENST00000373053.8	NP_612366.1
MCU	NM_001270679.2	c.22T>A	p.Ser8Thr	missense_variant	Exon 1 of 8		NP_001257608.1
MCU	NR_073062.2	n.31T>A		non_coding_transcript_exon_variant	Exon 1 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCU	ENST00000373053.8	c.22T>A	p.Ser8Thr	missense_variant	Exon 1 of 8	1	NM_138357.3	ENSP00000362144.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000441 AC: 5 AN: 1134672 Hom.: 0 Cov.: 30 AF XY: 0.00000739 AC XY: 4 AN XY: 540910

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: 0.00000425

Gnomad4 OTH exome AF: 0.0000221

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000928 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22T>A (p.S8T) alteration is located in exon 1 (coding exon 1) of the MCU gene. This alteration results from a T to A substitution at nucleotide position 22, causing the serine (S) at amino acid position 8 to be replaced by a threonine (T). 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	0.17
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.092
Sift	Uncertain	0.024	D;D
Sift4G	Benign	0.22	T;T
Polyphen		0.81	P;P
Vest4		0.50
MutPred		0.20		Loss of phosphorylation at S8 (P = 0.0418);Loss of phosphorylation at S8 (P = 0.0418);
MVP		0.24
MPC		0.56
ClinPred		0.55	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.32
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs745829005; hg19: chr10-74451931;