4-83264305-C-T

Position:

• chr4-83264305-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001358921.2(COQ2):​c.1010G>A​(p.Arg337Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,460,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: COQ2 NM_001358921.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 5.87

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36017698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COQ2	NM_001358921.2	c.1010G>A	p.Arg337Gln	missense_variant	7/7	ENST00000647002.2	NP_001345850.1
COQ2	NM_015697.9	c.1160G>A	p.Arg387Gln	missense_variant	7/7		NP_056512.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COQ2	ENST00000647002.2	c.1010G>A	p.Arg337Gln	missense_variant	7/7		NM_001358921.2	ENSP00000495761	P2
COQ2	ENST00000311469.9	c.1160G>A	p.Arg387Gln	missense_variant	7/7	1		ENSP00000310873	A2
COQ2	ENST00000503915.5	c.*142G>A		3_prime_UTR_variant, NMD_transcript_variant	7/7	1		ENSP00000427146
COQ2	ENST00000503391.5	c.*176-1650G>A		intron_variant, NMD_transcript_variant		2		ENSP00000426242

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000202 AC: 5 AN: 247524 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134262

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000685 AC: 10 AN: 1460074 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726212

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000135

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: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 387 of the COQ2 protein (p.Arg387Gln). This variant is present in population databases (rs763562410, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with COQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 60539). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COQ2 protein function. Experimental studies have shown that this missense change affects COQ2 function (PMID: 23758206). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Multiple system atrophy Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 18, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Benign	0.93
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;.
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	.;N
REVEL	Uncertain	0.45
Sift	Benign	0.087	.;T
Sift4G	Benign	0.31	.;T
Vest4		0.48
MutPred		0.69		Gain of sheet (P = 0.0827);.;
MVP		0.63
MPC		0.28
ClinPred		0.39	T
GERP RS		2.6
gMVP		0.61

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: rs763562410; hg19: chr4-84185458;