rs566165293

Variant names:

• chr4-83284628-G-A
• rs566165293
• NM_001358921.2:c.137C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-83284628-G-A
• chr4-83284628-G-C
• chr4-83284628-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001358921.2(COQ2):​c.137C>T​(p.Pro46Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,514,666 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P46S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: COQ2 NM_001358921.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.979
• Publications: 4 publications found

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: G2P, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010337204).
• BP6: Variant 4-83284628-G-A is Benign according to our data. Variant chr4-83284628-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 214223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00175 (266/152146) while in subpopulation AFR AF = 0.00616 (256/41558). AF 95% confidence interval is 0.00554. There are 0 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.137C>T	p.Pro46Leu	missense	Exon 1 of 7	NP_001345850.1	Q96H96-1
	COQ2	NM_015697.9		c.287C>T	p.Pro96Leu	missense	Exon 1 of 7	NP_056512.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ2	ENST00000647002.2	MANE Select	c.137C>T	p.Pro46Leu	missense	Exon 1 of 7	ENSP00000495761.2	Q96H96-1
	COQ2	ENST00000311469.9	TSL:1	c.287C>T	p.Pro96Leu	missense	Exon 1 of 7	ENSP00000310873.4	Q96H96-4
	COQ2	ENST00000311461.7	TSL:5	c.137C>T	p.Pro46Leu	missense	Exon 1 of 7	ENSP00000311835.7	Q96H96-3

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152040 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00615

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000171 AC: 17 AN: 99398 AF XY: 0.0000901

Gnomad AFR exome AF: 0.00868

Gnomad AMR exome AF: 0.000266

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: 0.000153 AC: 209 AN: 1362520 Hom.: 2 Cov.: 84 AF XY: 0.000141 AC XY: 95 AN XY: 671566

African (AFR) AF: 0.00616 AC: 169 AN: 27436

American (AMR) AF: 0.000374 AC: 12 AN: 32048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23864

East Asian (EAS) AF: 0.00 AC: 0 AN: 31360

South Asian (SAS) AF: 0.0000658 AC: 5 AN: 76012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45394

Middle Eastern (MID) AF: 0.000622 AC: 3 AN: 4826

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065152

Other (OTH) AF: 0.000354 AC: 20 AN: 56428

GnomAD4 genome AF: 0.00175 AC: 266 AN: 152146 Hom.: 0 Cov.: 34 AF XY: 0.00184 AC XY: 137 AN XY: 74376

African (AFR) AF: 0.00616 AC: 256 AN: 41558

American (AMR) AF: 0.000523 AC: 8 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67946

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.0000766 Hom.: 0

Bravo AF: 0.00197

ExAC AF: 0.000159 AC: 11

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	COQ2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.073	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.90	T
PhyloP100		0.98
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.070
Sift	Benign	0.059	T
Sift4G	Uncertain	0.056	T
Polyphen		0.047	B
Vest4		0.13
MVP		0.71
MPC		0.17
ClinPred		0.017	T
GERP RS		-0.27
PromoterAI		-0.0077	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
gMVP		0.33
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs566165293; hg19: chr4-84205781; COSMIC: COSV61021977; COSMIC: COSV61021977;