4-83284851-T-C

Variant names:

• chr4-83284851-T-C
• rs112033303
• ENST00000311469.9:c.64A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015697.9(COQ2):​c.64A>G​(p.Arg22Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,394,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 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. R22K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COQ2 NM_015697.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.50
• Publications: 21 publications found

Genes affected

COQ2 (HGNC:25223): (coenzyme Q2, polyprenyltransferase) This gene encodes an enzyme that functions in the final steps in the biosynthesis of CoQ (ubiquinone), a redox carrier in the mitochondrial respiratory chain and a lipid-soluble antioxidant. This enzyme, which is part of the coenzyme Q10 pathway, catalyzes the prenylation of parahydroxybenzoate with an all-trans polyprenyl group. Mutations in this gene cause coenzyme Q10 deficiency, a mitochondrial encephalomyopathy, and also COQ2 nephropathy, an inherited form of mitochondriopathy with primary renal involvement. [provided by RefSeq, Oct 2009]

COQ2 Gene-Disease associations (from GenCC):

• coenzyme Q10 deficiency, primary, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• multiple system atrophy

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• Leigh syndrome with nephrotic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04284668).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015697.9. 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
	COQ2	NM_015697.9		c.64A>G	p.Arg22Gly	missense	Exon 1 of 7	NP_056512.5
	COQ2	NM_001358921.2	MANE Select	c.-87A>G		upstream_gene	N/A	NP_001345850.1	Q96H96-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ2	ENST00000311469.9	TSL:1	c.64A>G	p.Arg22Gly	missense	Exon 1 of 7	ENSP00000310873.4	Q96H96-4
	COQ2	ENST00000647002.2	MANE Select	c.-87A>G		upstream_gene	N/A	ENSP00000495761.2	Q96H96-1
	COQ2	ENST00000311461.7	TSL:5	c.-87A>G		upstream_gene	N/A	ENSP00000311835.7	Q96H96-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1394702 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 689652

African (AFR) AF: 0.00 AC: 0 AN: 31520

American (AMR) AF: 0.00 AC: 0 AN: 36856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25290

East Asian (EAS) AF: 0.00 AC: 0 AN: 35862

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35978

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085824

Other (OTH) AF: 0.00 AC: 0 AN: 58446

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.56
DANN	Benign	0.95
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0054	N
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.93	T
PhyloP100		-3.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.096
Sift	Benign	1.0	T
Sift4G	Pathogenic	0.0	D
Vest4		0.11
MutPred		0.28		Loss of MoRF binding (P = 0.007)
MVP		0.23
MPC		0.33
ClinPred		0.066	T
GERP RS		-4.1
PromoterAI		0.14	Neutral
gMVP		0.23
Mutation Taster		=97/3	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: rs112033303; hg19: chr4-84206004;