4-83264287-A-G

Position:

• chr4-83264287-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001358921.2(COQ2):​c.1028T>C​(p.Val343Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,612,214 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (25 hom.)
• Consequence: COQ2 NM_001358921.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 8.94

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008151174).
• BP6: Variant 4-83264287-A-G is Benign according to our data. Variant chr4-83264287-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 214217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00188 (286/152270) while in subpopulation EAS AF= 0.0166 (86/5188). AF 95% confidence interval is 0.0137. There are 3 homozygotes in gnomad4. There are 162 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ2	NM_001358921.2	c.1028T>C	p.Val343Ala	missense_variant	7/7	ENST00000647002.2
COQ2	NM_015697.9	c.1178T>C	p.Val393Ala	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ2	ENST00000647002.2	c.1028T>C	p.Val343Ala	missense_variant	7/7		NM_001358921.2	P2
COQ2	ENST00000311469.9	c.1178T>C	p.Val393Ala	missense_variant	7/7	1		A2
COQ2	ENST00000503915.5	c.*160T>C		3_prime_UTR_variant, NMD_transcript_variant	7/7	1
COQ2	ENST00000503391.5	c.*176-1632T>C		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 152152 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0163

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00415 AC: 1027 AN: 247460 Hom.: 18 AF XY: 0.00328 AC XY: 440 AN XY: 134254

Gnomad AFR exome AF: 0.000454

Gnomad AMR exome AF: 0.0204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0158

Gnomad SAS exome AF: 0.000598

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000711

Gnomad OTH exome AF: 0.00284

GnomAD4 exome AF: 0.00112 AC: 1640 AN: 1459944 Hom.: 25 Cov.: 30 AF XY: 0.00103 AC XY: 747 AN XY: 726142

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0183

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0166

Gnomad4 SAS exome AF: 0.000548

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152270 Hom.: 3 Cov.: 32 AF XY: 0.00218 AC XY: 162 AN XY: 74462

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0166

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000827 Hom.: 3

Bravo AF: 0.00289

ExAC AF: 0.00363 AC: 439

Asia WGS AF: 0.00376 AC: 13 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Benign	0.92
Eigen	Benign	0.16
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;.
MetaRNN	Benign	0.0082	T;T
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
Vest4		0.36
MVP		0.79
MPC		0.20
ClinPred		0.072	T
GERP RS		6.2
gMVP		0.52

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: rs148156462; hg19: chr4-84185440;