rs566165293

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 12/19 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

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

Conservation

PhyloP100: 0.979

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 214223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-83284628-G-A is described in Lovd as [Benign]. Variant chr4-83284628-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ2	NM_001358921.2 linkuse as main transcript	c.137C>T	p.Pro46Leu	missense_variant	1/7	ENST00000647002.2
COQ2	NM_015697.9 linkuse as main transcript	c.287C>T	p.Pro96Leu	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ2	ENST00000647002.2 linkuse as main transcript	c.137C>T	p.Pro46Leu	missense_variant	1/7		NM_001358921.2	P2	Q96H96-1
COQ2	ENST00000311469.9 linkuse as main transcript	c.287C>T	p.Pro96Leu	missense_variant	1/7	1		A2	Q96H96-4
COQ2	ENST00000311461.7 linkuse as main transcript	c.137C>T	p.Pro46Leu	missense_variant	1/7	5			Q96H96-3
COQ2	ENST00000503391.5 linkuse as main transcript	c.137C>T	p.Pro46Leu	missense_variant, NMD_transcript_variant	1/7	2

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

GnomAD3 exomes

AF:

0.000171

AC:

AN:

99398

Hom.:

AF XY:

0.0000901

AC XY:

AN XY:

55508

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 SAS exome

AF:

0.0000543

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

Gnomad4 AFR exome

AF:

0.00616

Gnomad4 AMR exome

AF:

0.000374

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000658

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000354

GnomAD4 genome

AF:

0.00175

AC:

266

AN:

152146

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

137

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00616

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.0000766

Hom.:

Bravo

AF:

0.00197

ExAC

AF:

0.000159

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

COQ2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2021

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

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

MutationTaster

Benign

1.0

N;N;N

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

gMVP

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over