chr4-83269878-A-G

Variant names:

• chr4-83269878-A-G
• rs6535454
• NM_001358921.2:c.744T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001358921.2(COQ2):​c.744T>C​(p.Asp248Asp) 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:11
• 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
COQ2	NM_001358921.2	c.744T>C	p.Asp248Asp	synonymous_variant	Exon 5 of 7	ENST00000647002.2	NP_001345850.1
COQ2	NM_015697.9	c.894T>C	p.Asp298Asp	synonymous_variant	Exon 5 of 7		NP_056512.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COQ2	ENST00000647002.2	c.744T>C	p.Asp248Asp	synonymous_variant	Exon 5 of 7		NM_001358921.2	ENSP00000495761.2

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

GnomAD2 exomes AF: 0.735 AC: 177117 AN: 240834 AF XY: 0.735

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 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

African (AFR) AF: 0.814 AC: 26744 AN: 32844

American (AMR) AF: 0.697 AC: 29919 AN: 42940

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 17657 AN: 25998

East Asian (EAS) AF: 0.840 AC: 32791 AN: 39024

South Asian (SAS) AF: 0.746 AC: 62670 AN: 84022

European-Finnish (FIN) AF: 0.793 AC: 42274 AN: 53340

Middle Eastern (MID) AF: 0.700 AC: 4016 AN: 5740

European-Non Finnish (NFE) AF: 0.704 AC: 776622 AN: 1102958

Other (OTH) AF: 0.724 AC: 43286 AN: 59798

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

African (AFR) AF: 0.804 AC: 33391 AN: 41506

American (AMR) AF: 0.717 AC: 10953 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 2373 AN: 3470

East Asian (EAS) AF: 0.852 AC: 4413 AN: 5182

South Asian (SAS) AF: 0.741 AC: 3574 AN: 4820

European-Finnish (FIN) AF: 0.809 AC: 8571 AN: 10590

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.709 AC: 48189 AN: 67986

Other (OTH) AF: 0.738 AC: 1558 AN: 2110

Alfa AF: 0.722 Hom.: 86766

Bravo AF: 0.744

Asia WGS AF: 0.809 AC: 2817 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jul 01, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 11, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Coenzyme Q10 deficiency, primary, 1 Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.0
DANN	Benign	0.36
Mutation Taster		=82/18	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

Publications

LitVar

Other links and lift over

dbSNP: rs6535454; hg19: chr4-84191031;