rs6535454

Positions:

• chr4-83269878-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001358921.2(COQ2):​c.744T>C​(p.Asp248=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 1,598,806 control chromosomes in the GnomAD database, including 415,024 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42874 hom., cov: 32)
  • Exomes 𝑓: 0.72 (372150 hom.)
• Consequence: COQ2 NM_001358921.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.24

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 4-83269878-A-G is Benign according to our data. Variant chr4-83269878-A-G is described in ClinVar as [Benign]. Clinvar id is 128829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-83269878-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.831 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ2	NM_001358921.2	c.744T>C	p.Asp248=	synonymous_variant	5/7	ENST00000647002.2
COQ2	NM_015697.9	c.894T>C	p.Asp298=	synonymous_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ2	ENST00000647002.2	c.744T>C	p.Asp248=	synonymous_variant	5/7		NM_001358921.2	P2

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113854 AN: 152024 Hom.: 42844 Cov.: 32

Gnomad AFR AF: 0.805

Gnomad AMI AF: 0.772

Gnomad AMR AF: 0.717

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.742

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.738

GnomAD3 exomes AF: 0.735 AC: 177117 AN: 240834 Hom.: 65446 AF XY: 0.735 AC XY: 96265 AN XY: 131044

Gnomad AFR exome AF: 0.817

Gnomad AMR exome AF: 0.700

Gnomad ASJ exome AF: 0.680

Gnomad EAS exome AF: 0.847

Gnomad SAS exome AF: 0.743

Gnomad FIN exome AF: 0.794

Gnomad NFE exome AF: 0.710

Gnomad OTH exome AF: 0.719

GnomAD4 exome AF: 0.716 AC: 1035979 AN: 1446664 Hom.: 372150 Cov.: 32 AF XY: 0.718 AC XY: 516508 AN XY: 719836

Gnomad4 AFR exome AF: 0.814

Gnomad4 AMR exome AF: 0.697

Gnomad4 ASJ exome AF: 0.679

Gnomad4 EAS exome AF: 0.840

Gnomad4 SAS exome AF: 0.746

Gnomad4 FIN exome AF: 0.793

Gnomad4 NFE exome AF: 0.704

Gnomad4 OTH exome AF: 0.724

GnomAD4 genome AF: 0.749 AC: 113936 AN: 152142 Hom.: 42874 Cov.: 32 AF XY: 0.754 AC XY: 56071 AN XY: 74382

Gnomad4 AFR AF: 0.804

Gnomad4 AMR AF: 0.717

Gnomad4 ASJ AF: 0.684

Gnomad4 EAS AF: 0.852

Gnomad4 SAS AF: 0.741

Gnomad4 FIN AF: 0.809

Gnomad4 NFE AF: 0.709

Gnomad4 OTH AF: 0.738

Alfa AF: 0.718 Hom.: 24335

Bravo AF: 0.744

Asia WGS AF: 0.809 AC: 2817 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 95% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 88. Only high quality variants are reported. -

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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 11, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.0
DANN	Benign	0.36

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: rs6535454; hg19: chr4-84191031;