12-53665418-G-C

Variant names:

• chr12-53665418-G-C
• rs1944886727
• NM_005176.7:c.322C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005176.7(ATP5MC2):​c.322C>G​(p.Leu108Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP5MC2 NM_005176.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.89

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP5MC2	NM_005176.7	c.322C>G	p.Leu108Val	missense_variant	Exon 5 of 5	ENST00000394349.9	NP_005167.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP5MC2	ENST00000394349.9	c.322C>G	p.Leu108Val	missense_variant	Exon 5 of 5	2	NM_005176.7	ENSP00000377878.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461352 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727036

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.493C>G (p.L165V) alteration is located in exon 5 (coding exon 5) of the ATP5G2 gene. This alteration results from a C to G substitution at nucleotide position 493, causing the leucine (L) at amino acid position 165 to be replaced by a valine (V). 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	Uncertain	0.55
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T;T;T;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	.;.;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.8	L;L;L;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.8	.;.;D;D;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.020	.;.;D;D;.
Sift4G	Uncertain	0.032	.;D;D;D;.
Polyphen		1.0	D;D;D;D;D
Vest4		0.68, 0.68, 0.69
MutPred		0.67		Gain of catalytic residue at L108 (P = 0.0303);Gain of catalytic residue at L108 (P = 0.0303);Gain of catalytic residue at L108 (P = 0.0303);.;.;
MVP		0.81
MPC		0.96
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.35
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

LitVar

Other links and lift over

dbSNP: rs1944886727; hg19: chr12-54059202;