rs6818847

chr4-83284719-C-A

Variant summary

Our verdict is Benign. Variant got -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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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:12
• Conservation: PhyloP100: -1.25

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 128828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-83284719-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ2	NM_001358921.2	c.46G>T	p.Val16Leu	missense_variant	1/7	ENST00000647002.2
COQ2	NM_015697.9	c.196G>T	p.Val66Leu	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ2	ENST00000647002.2	c.46G>T	p.Val16Leu	missense_variant	1/7		NM_001358921.2	P2
COQ2	ENST00000311469.9	c.196G>T	p.Val66Leu	missense_variant	1/7	1		A2
COQ2	ENST00000311461.7	c.46G>T	p.Val16Leu	missense_variant	1/7	5
COQ2	ENST00000503391.5	c.46G>T	p.Val16Leu	missense_variant, NMD_transcript_variant	1/7	2

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

GnomAD3 exomes AF: 0.716 AC: 75123 AN: 104870 Hom.: 27189 AF XY: 0.719 AC XY: 42283 AN XY: 58772

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 SAS exome AF: 0.733

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

Gnomad4 AFR exome AF: 0.422

Gnomad4 AMR exome AF: 0.674

Gnomad4 ASJ exome AF: 0.650

Gnomad4 EAS exome AF: 0.885

Gnomad4 SAS exome AF: 0.733

Gnomad4 FIN exome AF: 0.790

Gnomad4 NFE exome AF: 0.696

Gnomad4 OTH exome AF: 0.686

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

Gnomad4 AFR AF: 0.424

Gnomad4 AMR AF: 0.675

Gnomad4 ASJ AF: 0.656

Gnomad4 EAS AF: 0.870

Gnomad4 SAS AF: 0.725

Gnomad4 FIN AF: 0.804

Gnomad4 NFE AF: 0.699

Gnomad4 OTH AF: 0.651

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

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Coenzyme Q10 deficiency, primary, 1 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.34	T;.;T
MetaRNN	Benign	9.6e-7	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Pathogenic	0.80	T
Polyphen		0.0	.;.;B
Vest4		0.11, 0.057
MutPred		0.38		Gain of disorder (P = 0.0309);.;Gain of disorder (P = 0.0309);
MPC		0.15
ClinPred		0.0016	T
GERP RS		-2.7
gMVP		0.087

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