12-53669311-G-T

Variant names:

• chr12-53669311-G-T
• rs199978143
• NM_005176.7:c.148C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005176.7(ATP5MC2):​c.148C>A​(p.Leu50Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. L50F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP5MC2 NM_005176.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.344

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17886871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP5MC2	NM_005176.7	c.148C>A	p.Leu50Ile	missense_variant	Exon 4 of 5	ENST00000394349.9	NP_005167.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP5MC2	ENST00000394349.9	c.148C>A	p.Leu50Ile	missense_variant	Exon 4 of 5	2	NM_005176.7	ENSP00000377878.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461660 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.010	T;T;T;.;.
Eigen	Benign	-0.022
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.28	.;.;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;M;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.54	.;.;N;N;.
REVEL	Benign	0.076
Sift	Benign	0.13	.;.;T;T;.
Sift4G	Benign	0.27	.;T;T;T;.
Polyphen		0.98	D;D;D;P;D
Vest4		0.091, 0.089
MutPred		0.30		Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);.;.;
MVP		0.47
MPC		0.88
ClinPred		0.51	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.45

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: rs199978143; hg19: chr12-54063095;