chr4-83284628-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001358921.2(COQ2):c.137C>T(p.Pro46Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,514,666 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P46S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00015 ( 2 hom. )

Consequence

COQ2
NM_001358921.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.979

Publications

4 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), G2P
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

COQ2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010337204).

BP6

Variant 4-83284628-G-A is Benign according to our data. Variant chr4-83284628-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 214223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00175 (266/152146) while in subpopulation AFR AF = 0.00616 (256/41558). AF 95% confidence interval is 0.00554. There are 0 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ2	NM_001358921.2 link	c.137C>T	p.Pro46Leu	missense_variant	Exon 1 of 7	ENST00000647002.2	NP_001345850.1
COQ2	NM_015697.9 link	c.287C>T	p.Pro96Leu	missense_variant	Exon 1 of 7		NP_056512.5	Q96H96-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COQ2	ENST00000647002.2 link	c.137C>T	p.Pro46Leu	missense_variant	Exon 1 of 7		NM_001358921.2	ENSP00000495761.2	Q96H96-1
COQ2	ENST00000311469.9 link	c.287C>T	p.Pro96Leu	missense_variant	Exon 1 of 7	1		ENSP00000310873.4	Q96H96-4
COQ2	ENST00000311461.7 link	c.137C>T	p.Pro46Leu	missense_variant	Exon 1 of 7	5		ENSP00000311835.7	Q96H96-3E2QRG7
COQ2	ENST00000503391.5 link	n.137C>T		non_coding_transcript_exon_variant	Exon 1 of 7	2		ENSP00000426242.1	E7EPM7

Frequencies

GnomAD3 genomes

AF:

0.00175

AC:

266

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00615

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000171

AC:

AN:

99398

AF XY:

0.0000901

show subpopulations

Gnomad AFR exome

AF:

0.00868

Gnomad AMR exome

AF:

0.000266

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000153

AC:

209

AN:

1362520

Hom.:

Cov.:

AF XY:

0.000141

AC XY:

AN XY:

671566

show subpopulations

African (AFR)

AF:

0.00616

AC:

169

AN:

27436

American (AMR)

AF:

0.000374

AC:

AN:

32048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23864

East Asian (EAS)

AF:

0.00

AC:

AN:

31360

South Asian (SAS)

AF:

0.0000658

AC:

AN:

76012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45394

Middle Eastern (MID)

AF:

0.000622

AC:

AN:

4826

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1065152

Other (OTH)

AF:

0.000354

AC:

AN:

56428

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00175

AC:

266

AN:

152146

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

137

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.00616

AC:

256

AN:

41558

American (AMR)

AF:

0.000523

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67946

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000766

Hom.:

Bravo

AF:

0.00197

ExAC

AF:

0.000159

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 21, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

COQ2-related disorder

Benign:1

Oct 21, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

7.4

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.073

.;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.47

T;.;T

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-0.90

PhyloP100

0.98

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.60

.;N;N

REVEL

Benign

0.070

Sift

Benign

0.059

.;T;T

Sift4G

Uncertain

0.056

.;T;T

Polyphen

0.047

.;.;B

Vest4

0.13, 0.16

MVP

0.71

MPC

0.17

ClinPred

0.017

GERP RS

-0.27

PromoterAI

-0.0077

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

gMVP

0.33

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over