rs778094136

Variant names:

• chr4-83284533-T-C
• rs778094136
• NM_001358921.2:c.232A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-83284533-T-C
• chr4-83284533-T-A
• chr4-83284533-T-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 4P and 6B. PS3 BP4_Moderate BS1

The NM_001358921.2(COQ2):​c.232A>G​(p.Met78Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000165 in 1,576,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002556118: the variant could not rescue growth in a COQ2-null yeast strain (Multiple-System Atrophy Research Collaboration_2013)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M78T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: COQ2 NM_001358921.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 O:2
• Conservation: PhyloP100: 4.62
• Publications: 24 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: Likely_benign. The variant received -2 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002556118: the variant could not rescue growth in a COQ2-null yeast strain (Multiple-System Atrophy Research Collaboration_2013); COQ2-null yeast expressing the the variant had decreased expression of other Coenzyme Q genes (COQ6, Desbats_2016); COQ2-null yeast had reduced oxygen consumption rate compared to wild-type (Yasuda_2019).
• BP4: Computational evidence support a benign effect (MetaRNN=0.14514425).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000263 (4/151932) while in subpopulation EAS AF = 0.000581 (3/5166). AF 95% confidence interval is 0.000158. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

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.232A>G	p.Met78Val	missense	Exon 1 of 7	NP_001345850.1	Q96H96-1
	COQ2	NM_015697.9		c.382A>G	p.Met128Val	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.232A>G	p.Met78Val	missense	Exon 1 of 7	ENSP00000495761.2	Q96H96-1
	COQ2	ENST00000311469.9	TSL:1	c.382A>G	p.Met128Val	missense	Exon 1 of 7	ENSP00000310873.4	Q96H96-4
	COQ2	ENST00000311461.7	TSL:5	c.232A>G	p.Met78Val	missense	Exon 1 of 7	ENSP00000311835.7	Q96H96-3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151932 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000495 AC: 9 AN: 181648 AF XY: 0.0000199

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000594

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000154 AC: 22 AN: 1424446 Hom.: 0 Cov.: 84 AF XY: 0.0000113 AC XY: 8 AN XY: 705924

African (AFR) AF: 0.00 AC: 0 AN: 31560

American (AMR) AF: 0.00 AC: 0 AN: 40126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25328

East Asian (EAS) AF: 0.000243 AC: 9 AN: 37102

South Asian (SAS) AF: 0.00 AC: 0 AN: 81546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.0000110 AC: 12 AN: 1095066

Other (OTH) AF: 0.0000170 AC: 1 AN: 58904

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151932 Hom.: 0 Cov.: 34 AF XY: 0.0000539 AC XY: 4 AN XY: 74212

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

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

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67890

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000122 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000433 AC: 5

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
1	-	-	Coenzyme Q10 deficiency, primary, 1 (1)
-	1	-	Coenzyme Q10 deficiency, primary, 1;C3714927:Multiple system atrophy 1, susceptibility to (1)
-	1	-	Inborn genetic diseases (1)
-	-	-	Coenzyme Q10 deficiency (1)
-	-	-	Multiple system atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Benign	0.65
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.43	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.61	T
PhyloP100		4.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.35
Sift	Benign	0.10	T
Sift4G	Benign	0.66	T
Polyphen		0.13	B
Vest4		0.73
MutPred		0.44		Loss of glycosylation at P73 (P = 0.0474)
MVP		0.63
MPC		0.18
ClinPred		0.12	T
GERP RS		2.2
PromoterAI		-0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.73
Mutation Taster		=19/81	disease causing (ClinVar)

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: rs778094136; hg19: chr4-84205686;