chr4-83284719-C-A

Variant names:

• chr4-83284719-C-A
• rs6818847
• NM_001358921.2:c.46G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001358921.2(COQ2):​c.46G>T​(p.Val16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,506,450 control chromosomes in the GnomAD database, including 363,568 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V16V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.63 (31940 hom., cov: 33)
  • Exomes 𝑓: 0.70 (331628 hom.)
• Consequence: COQ2 NM_001358921.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.25
• Publications: 34 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.564486E-7).
• BP6: Variant 4-83284719-C-A is Benign according to our data. Variant chr4-83284719-C-A is described in ClinVar as Benign. ClinVar VariationId is 128828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001358921.2. 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_001358921.2	MANE Select	c.46G>T	p.Val16Leu	missense	Exon 1 of 7	NP_001345850.1	Q96H96-1
	COQ2	NM_015697.9		c.196G>T	p.Val66Leu	missense	Exon 1 of 7	NP_056512.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ2	ENST00000647002.2	MANE Select	c.46G>T	p.Val16Leu	missense	Exon 1 of 7	ENSP00000495761.2	Q96H96-1
	COQ2	ENST00000311469.9	TSL:1	c.196G>T	p.Val66Leu	missense	Exon 1 of 7	ENSP00000310873.4	Q96H96-4
	COQ2	ENST00000311461.7	TSL:5	c.46G>T	p.Val16Leu	missense	Exon 1 of 7	ENSP00000311835.7	Q96H96-3

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96252 AN: 151874 Hom.: 31938 Cov.: 33

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.725

Gnomad FIN AF: 0.804

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.699

Gnomad OTH AF: 0.651

GnomAD2 exomes AF: 0.716 AC: 75123 AN: 104870 AF XY: 0.719

Gnomad AFR exome AF: 0.447

Gnomad AMR exome AF: 0.688

Gnomad ASJ exome AF: 0.659

Gnomad EAS exome AF: 0.885

Gnomad FIN exome AF: 0.790

Gnomad NFE exome AF: 0.707

Gnomad OTH exome AF: 0.693

GnomAD4 exome AF: 0.698 AC: 944870 AN: 1354464 Hom.: 331628 Cov.: 70 AF XY: 0.700 AC XY: 467584 AN XY: 667978

African (AFR) AF: 0.422 AC: 11703 AN: 27750

American (AMR) AF: 0.674 AC: 20809 AN: 30882

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 15698 AN: 24152

East Asian (EAS) AF: 0.885 AC: 27793 AN: 31400

South Asian (SAS) AF: 0.733 AC: 55399 AN: 75610

European-Finnish (FIN) AF: 0.790 AC: 29691 AN: 37560

Middle Eastern (MID) AF: 0.621 AC: 3270 AN: 5268

European-Non Finnish (NFE) AF: 0.696 AC: 741788 AN: 1065440

Other (OTH) AF: 0.686 AC: 38719 AN: 56402

GnomAD4 genome AF: 0.633 AC: 96270 AN: 151986 Hom.: 31940 Cov.: 33 AF XY: 0.642 AC XY: 47705 AN XY: 74304

African (AFR) AF: 0.424 AC: 17575 AN: 41484

American (AMR) AF: 0.675 AC: 10312 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2277 AN: 3470

East Asian (EAS) AF: 0.870 AC: 4478 AN: 5146

South Asian (SAS) AF: 0.725 AC: 3501 AN: 4830

European-Finnish (FIN) AF: 0.804 AC: 8490 AN: 10554

Middle Eastern (MID) AF: 0.620 AC: 181 AN: 292

European-Non Finnish (NFE) AF: 0.699 AC: 47485 AN: 67908

Other (OTH) AF: 0.651 AC: 1372 AN: 2108

Alfa AF: 0.664 Hom.: 5971

Bravo AF: 0.613

TwinsUK AF: 0.711 AC: 2638

ALSPAC AF: 0.688 AC: 2653

ESP6500AA AF: 0.549 AC: 1570

ESP6500EA AF: 0.746 AC: 4779

ExAC AF: 0.614 AC: 44725

Asia WGS AF: 0.774 AC: 2692 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	2	Coenzyme Q10 deficiency, primary, 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.33
DANN	Benign	0.60
DEOGEN2	Benign	0.077	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	9.6e-7	T
MetaSVM	Benign	-0.99	T
PhyloP100		-1.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.068
Sift	Benign	1.0	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.38		Gain of disorder (P = 0.0309)
MPC		0.15
ClinPred		0.0016	T
GERP RS		-2.7
PromoterAI		-0.087	Neutral
gMVP		0.087
Mutation Taster		=100/0	polymorphism (auto)

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: rs6818847; hg19: chr4-84205872; COSMIC: COSV61021909; COSMIC: COSV61021909;