4-83284851-T-G

Variant names:

• chr4-83284851-T-G
• rs112033303
• ENST00000311469.9:c.64A>C

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_015697.9(COQ2):​c.64A>C​(p.Arg22Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000534 in 1,547,008 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (11 hom.)
• Consequence: COQ2 NM_015697.9 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.50
• Publications: 21 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=-0.92).
• BP6: Variant 4-83284851-T-G is Benign according to our data. Variant chr4-83284851-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000512 (78/152312) while in subpopulation AMR AF = 0.00496 (76/15314). AF 95% confidence interval is 0.00406. There are 1 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015697.9. 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_015697.9		c.64A>C	p.Arg22Arg	synonymous	Exon 1 of 7	NP_056512.5
	COQ2	NM_001358921.2	MANE Select	c.-87A>C		upstream_gene	N/A	NP_001345850.1	Q96H96-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ2	ENST00000311469.9	TSL:1	c.64A>C	p.Arg22Arg	synonymous	Exon 1 of 7	ENSP00000310873.4	Q96H96-4
	COQ2	ENST00000647002.2	MANE Select	c.-87A>C		upstream_gene	N/A	ENSP00000495761.2	Q96H96-1
	COQ2	ENST00000311461.7	TSL:5	c.-87A>C		upstream_gene	N/A	ENSP00000311835.7	Q96H96-3

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 78 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00395 AC: 609 AN: 154366 AF XY: 0.00279

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0245

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000910

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00208

GnomAD4 exome AF: 0.000536 AC: 748 AN: 1394696 Hom.: 11 Cov.: 33 AF XY: 0.000431 AC XY: 297 AN XY: 689648

African (AFR) AF: 0.00 AC: 0 AN: 31520

American (AMR) AF: 0.0199 AC: 732 AN: 36850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25290

East Asian (EAS) AF: 0.00 AC: 0 AN: 35862

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1085824

Other (OTH) AF: 0.000222 AC: 13 AN: 58446

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.000456 AC XY: 34 AN XY: 74486

African (AFR) AF: 0.0000241 AC: 1 AN: 41572

American (AMR) AF: 0.00496 AC: 76 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000147 Hom.: 3

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.47
DANN	Benign	0.43
PhyloP100		-3.5
PromoterAI		0.15	Neutral
Mutation Taster		=100/0	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: rs112033303; hg19: chr4-84206004;