12-53665364-T-G

Position:

• chr12-53665364-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005176.7(ATP5MC2):​c.376A>C​(p.Met126Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP5MC2 NM_005176.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

ATP5MC2 (HGNC:842): (ATP synthase membrane subunit c locus 2) This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and single representatives of the gamma, delta, and epsilon subunits. The proton channel likely has nine subunits (a, b, c, d, e, f, g, F6 and 8). There are three separate genes which encode subunit c of the proton channel and they specify precursors with different import sequences but identical mature proteins. The protein encoded by this gene is one of three precursors of subunit c. This gene has multiple pseudogenes. [provided by RefSeq, Jan 2018]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP5MC2	NM_005176.7	c.376A>C	p.Met126Leu	missense_variant	5/5	ENST00000394349.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP5MC2	ENST00000394349.9	c.376A>C	p.Met126Leu	missense_variant	5/5	2	NM_005176.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2023

The c.547A>C (p.M183L) alteration is located in exon 5 (coding exon 5) of the ATP5G2 gene. This alteration results from a A to C substitution at nucleotide position 547, causing the methionine (M) at amino acid position 183 to be replaced by a leucine (L). 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	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	T;T;T;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.0059	T
MetaRNN	Uncertain	0.46	T;T;T;T;D;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.66	N;N;N;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
REVEL	Uncertain	0.36
Polyphen		0.0040	B;B;B;B;.;B
Vest4		0.67, 0.67, 0.66, 0.76
MutPred		0.42		Loss of catalytic residue at M126 (P = 0.0236);Loss of catalytic residue at M126 (P = 0.0236);Loss of catalytic residue at M126 (P = 0.0236);.;.;.;
MVP		0.53
MPC		0.28
ClinPred		0.80	D
GERP RS		5.3
Varity_R		0.43
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-54059148;