chr4-83284576-C-A

Variant names:

• chr4-83284576-C-A
• rs368507578
• NM_001358921.2:c.189G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001358921.2(COQ2):​c.189G>T​(p.Val63Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,553,630 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (11 hom., cov: 34)
  • Exomes 𝑓: 0.00066 (6 hom.)
• Consequence: COQ2 NM_001358921.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.63
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 4-83284576-C-A is Benign according to our data. Variant chr4-83284576-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00652 (992/152178) while in subpopulation AFR AF = 0.0224 (929/41552). AF 95% confidence interval is 0.0212. There are 11 homozygotes in GnomAd4. There are 466 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.189G>T	p.Val63Val	synonymous	Exon 1 of 7	NP_001345850.1	Q96H96-1
	COQ2	NM_015697.9		c.339G>T	p.Val113Val	synonymous	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.189G>T	p.Val63Val	synonymous	Exon 1 of 7	ENSP00000495761.2	Q96H96-1
	COQ2	ENST00000311469.9	TSL:1	c.339G>T	p.Val113Val	synonymous	Exon 1 of 7	ENSP00000310873.4	Q96H96-4
	COQ2	ENST00000311461.7	TSL:5	c.189G>T	p.Val63Val	synonymous	Exon 1 of 7	ENSP00000311835.7	Q96H96-3

Frequencies

GnomAD3 genomes AF: 0.00652 AC: 992 AN: 152066 Hom.: 11 Cov.: 34

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00109 AC: 159 AN: 145330 AF XY: 0.000813

Gnomad AFR exome AF: 0.0231

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000218

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.000664 AC: 930 AN: 1401452 Hom.: 6 Cov.: 84 AF XY: 0.000603 AC XY: 418 AN XY: 692790

African (AFR) AF: 0.0221 AC: 668 AN: 30160

American (AMR) AF: 0.00147 AC: 54 AN: 36710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24870

East Asian (EAS) AF: 0.00 AC: 0 AN: 35138

South Asian (SAS) AF: 0.0000377 AC: 3 AN: 79536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48210

Middle Eastern (MID) AF: 0.00182 AC: 10 AN: 5506

European-Non Finnish (NFE) AF: 0.000110 AC: 119 AN: 1083278

Other (OTH) AF: 0.00131 AC: 76 AN: 58044

GnomAD4 genome AF: 0.00652 AC: 992 AN: 152178 Hom.: 11 Cov.: 34 AF XY: 0.00626 AC XY: 466 AN XY: 74404

African (AFR) AF: 0.0224 AC: 929 AN: 41552

American (AMR) AF: 0.00262 AC: 40 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67966

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.000472 Hom.: 0

Bravo AF: 0.00766

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.13
DANN	Benign	0.65
PhyloP100		-4.6
PromoterAI		-0.11	Neutral
Mutation Taster		=99/1	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: rs368507578; hg19: chr4-84205729;