12-53669332-T-C

Variant names:

• chr12-53669332-T-C
• rs758757719
• NM_005176.7:c.127A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005176.7(ATP5MC2):​c.127A>G​(p.Ser43Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,460,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ATP5MC2 NM_005176.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0130
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03389865).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005176.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP5MC2	NM_005176.7	MANE Select	c.127A>G	p.Ser43Gly	missense	Exon 4 of 5	NP_005167.3	Q06055-1
	ATP5MC2	NM_001002031.4		c.175A>G	p.Ser59Gly	missense	Exon 4 of 5	NP_001002031.1	Q06055-3
	ATP5MC2	NM_001330269.2		c.127A>G	p.Ser43Gly	missense	Exon 4 of 5	NP_001317198.1	Q06055-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP5MC2	ENST00000394349.9	TSL:2 MANE Select	c.127A>G	p.Ser43Gly	missense	Exon 4 of 5	ENSP00000377878.5	Q06055-1
	ATP5MC2	ENST00000552242.5	TSL:1	c.127A>G	p.Ser43Gly	missense	Exon 5 of 6	ENSP00000448801.2	Q06055-1
	ATP5MC2	ENST00000495596.5	TSL:1	n.1534A>G		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000720 AC: 18 AN: 250128 AF XY: 0.0000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000526

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1460804 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726706

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.000427 AC: 19 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111528

Other (OTH) AF: 0.0000331 AC: 2 AN: 60356

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.0098	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.013
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.025
Sift	Benign	0.18	T
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.19
MutPred		0.23		Loss of glycosylation at S43 (P = 0.025)
MVP		0.41
MPC		0.25
ClinPred		0.039	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.040
gMVP		0.37
Mutation Taster		=85/15	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: rs758757719; hg19: chr12-54063116;