rs781062050

Variant names:

• chr12-53669254-C-G
• rs781062050
• NM_005176.7:c.205G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-53669254-C-G
• chr12-53669254-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005176.7(ATP5MC2):​c.205G>C​(p.Asp69His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D69N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ATP5MC2 NM_005176.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP5MC2	NM_005176.7	c.205G>C	p.Asp69His	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.205G>C	p.Asp69His	missense_variant	Exon 4 of 5	2	NM_005176.7	ENSP00000377878.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461820 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;T;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;.;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.3	M;M;M;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.1	.;.;D;D;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0040	.;.;D;D;.
Sift4G	Uncertain	0.011	.;D;D;D;.
Polyphen		1.0	D;D;D;D;D
Vest4		0.95, 0.94
MutPred		0.43		Gain of ubiquitination at K73 (P = 0.0831);Gain of ubiquitination at K73 (P = 0.0831);Gain of ubiquitination at K73 (P = 0.0831);.;.;
MVP		0.87
MPC		1.0
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.66
gMVP		0.96
Mutation Taster		=62/38	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: rs781062050; hg19: chr12-54063038; COSMIC: COSV104653785; COSMIC: COSV104653785;