rs150295921

chr4-83273601-T-C

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.437A>G(p.Asn146Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000955 in 1,613,438 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00052 (7 hom.)
• Consequence: COQ2 NM_001358921.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0620

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=0.010999858).
• BP6: Variant 4-83273601-T-C is Benign according to our data. Variant chr4-83273601-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 136973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-83273601-T-C is described in Lovd as [Benign]. Variant chr4-83273601-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00516 (785/152230) while in subpopulation AFR AF= 0.0179 (745/41522). AF 95% confidence interval is 0.0169. There are 2 homozygotes in gnomad4. There are 371 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ2	NM_001358921.2	c.437A>G	p.Asn146Ser	missense_variant	3/7	ENST00000647002.2
COQ2	NM_015697.9	c.587A>G	p.Asn196Ser	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ2	ENST00000647002.2	c.437A>G	p.Asn146Ser	missense_variant	3/7		NM_001358921.2	P2

Frequencies

GnomAD3 genomes AF: 0.00515 AC: 783 AN: 152112 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00134 AC: 333 AN: 248588 Hom.: 0 AF XY: 0.000867 AC XY: 117 AN XY: 134888

Gnomad AFR exome AF: 0.0181

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000985

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000517 AC: 756 AN: 1461208 Hom.: 7 Cov.: 30 AF XY: 0.000457 AC XY: 332 AN XY: 726890

Gnomad4 AFR exome AF: 0.0176

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00516 AC: 785 AN: 152230 Hom.: 2 Cov.: 31 AF XY: 0.00498 AC XY: 371 AN XY: 74438

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000927 Hom.: 4

Bravo AF: 0.00552

ESP6500AA AF: 0.0150 AC: 55

ESP6500EA AF: 0.000244 AC: 2

ExAC AF: 0.00156 AC: 189

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	COQ2: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 11, 2016	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	0.13
Dann	Benign	0.31
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.87	D;.;D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
Polyphen		0.0	.;.;B
Vest4		0.15, 0.15
MVP		0.54
MPC		0.12
ClinPred		0.00017	T
GERP RS		-1.0
gMVP		0.39

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: rs150295921; hg19: chr4-84194754; COSMIC: COSV61022436;