4-83284719-C-G

Variant names:

• chr4-83284719-C-G
• NM_001358921.2:c.46G>C
• COQ2 p.Val16Leu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001358921.2(COQ2):​c.46G>C​(p.Val16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V16V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COQ2 NM_001358921.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.069122165).

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.46G>C	p.Val16Leu	missense	Exon 1 of 7	NP_001345850.1	Q96H96-1
	COQ2	NM_015697.9		c.196G>C	p.Val66Leu	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.46G>C	p.Val16Leu	missense	Exon 1 of 7	ENSP00000495761.2	Q96H96-1
	COQ2	ENST00000311469.9	TSL:1	c.196G>C	p.Val66Leu	missense	Exon 1 of 7	ENSP00000310873.4	Q96H96-4
	COQ2	ENST00000311461.7	TSL:5	c.46G>C	p.Val16Leu	missense	Exon 1 of 7	ENSP00000311835.7	Q96H96-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1354584 Hom.: 0 Cov.: 70 AF XY: 0.00 AC XY: 0 AN XY: 668040

African (AFR) AF: 0.00 AC: 0 AN: 27758

American (AMR) AF: 0.00 AC: 0 AN: 30898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24156

East Asian (EAS) AF: 0.00 AC: 0 AN: 31406

South Asian (SAS) AF: 0.00 AC: 0 AN: 75618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5270

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065490

Other (OTH) AF: 0.00 AC: 0 AN: 56410

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.33
DANN	Benign	0.55
DEOGEN2	Benign	0.077	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0069	N
LIST_S2	Benign	0.34	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.90	T
PhyloP100		-1.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.067
Sift	Benign	1.0	T
Sift4G	Benign	0.53	T
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.087
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-84205872;