rs121918231

Positions:

chr4-83273598-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001358921.2(COQ2):c.440G>A(p.Arg147His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

COQ2
NM_001358921.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 7.68

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 4-83273598-C-T is Pathogenic according to our data. Variant chr4-83273598-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-83273598-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COQ2	NM_001358921.2 linkuse as main transcript	c.440G>A	p.Arg147His	missense_variant	3/7	ENST00000647002.2	NP_001345850.1
COQ2	NM_015697.9 linkuse as main transcript	c.590G>A	p.Arg197His	missense_variant	3/7		NP_056512.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COQ2	ENST00000647002.2 linkuse as main transcript	c.440G>A	p.Arg147His	missense_variant	3/7		NM_001358921.2	ENSP00000495761	P2	Q96H96-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000804

AC:

AN:

248740

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134954

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461220

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726876

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000279

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000828

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Coenzyme Q10 deficiency, primary, 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2007	- -
Likely pathogenic, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 04, 2018	- -

Coenzyme Q10 deficiency, primary, 1;C3714927:Multiple system atrophy 1, susceptibility to

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 14, 2021

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 30, 2020

Yeast complementation analyses showed failure of this variant to restore respiratory growth to wild type levels (Desbats et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33587123, 31216405, 28125198, 16400613, 29961769, 29296619, 17855635, 18235438, 27493029, 25525159) -

Coenzyme Q10 deficiency

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

.;.;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

D;.;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-4.9

.;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

.;D;D

Polyphen

1.0

.;.;D

Vest4

0.97, 0.96

MutPred

0.95

Loss of methylation at R147 (P = 0.0407);.;Loss of methylation at R147 (P = 0.0407);

MVP

0.99

MPC

0.75

ClinPred

1.0

GERP RS

5.6

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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