Genetic Variant COQ2:p.Met78Leu (chr4-83284533-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001358921.2(COQ2):c.232A>C(p.Met78Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000825 in 1,576,378 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M78V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

COQ2
NM_001358921.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.62

Publications

24 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001358921.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ2	NM_001358921.2	MANE Select	c.232A>C	p.Met78Leu	missense	Exon 1 of 7	NP_001345850.1
	COQ2	NM_015697.9		c.382A>C	p.Met128Leu	missense	Exon 1 of 7	NP_056512.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COQ2	ENST00000647002.2	MANE Select	c.232A>C	p.Met78Leu	missense	Exon 1 of 7	ENSP00000495761.2
COQ2	ENST00000311469.9	TSL:1	c.382A>C	p.Met128Leu	missense	Exon 1 of 7	ENSP00000310873.4
COQ2	ENST00000311461.7	TSL:5	c.232A>C	p.Met78Leu	missense	Exon 1 of 7	ENSP00000311835.7

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000551

AC:

AN:

181648

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000842

AC:

AN:

1424446

Hom.:

Cov.:

AF XY:

0.00000708

AC XY:

AN XY:

705924

show subpopulations

African (AFR)

AF:

0.0000634

AC:

AN:

31560

American (AMR)

AF:

0.00

AC:

AN:

40126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25328

East Asian (EAS)

AF:

0.00

AC:

AN:

37102

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49168

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.00000731

AC:

AN:

1095066

Other (OTH)

AF:

0.0000170

AC:

AN:

58904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151932

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74212

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41394

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67890

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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:

0.0000408

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000173

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.12

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.63

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.44

MetaSVM

Benign

-0.46

PhyloP100

4.6

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.38

Sift

Benign

0.057

Sift4G

Benign

0.19

Polyphen

0.13

Vest4

0.64

MutPred

0.56

Loss of helix (P = 0.0104)

MVP

0.66

MPC

0.17

ClinPred

0.41

GERP RS

2.2

PromoterAI

-0.038

Neutral

(source)

gMVP

0.67

Mutation Taster

=30/70

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over