NM_001358921.2:c.194A>C

Variant names:

• chr4-83284571-T-G
• rs375934957
• NM_001358921.2:c.194A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001358921.2(COQ2):​c.194A>C​(p.Asp65Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000936 in 1,557,410 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D65D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0053 (11 hom., cov: 34)
  • Exomes 𝑓: 0.00046 (4 hom.)
• Consequence: COQ2 NM_001358921.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.163
• 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: 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041458905).
• BP6: Variant 4-83284571-T-G is Benign according to our data. Variant chr4-83284571-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218722.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00534 (811/151770) while in subpopulation AFR AF = 0.0186 (770/41392). AF 95% confidence interval is 0.0175. There are 11 homozygotes in GnomAd4. There are 387 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ2	NM_001358921.2	MANE Select	c.194A>C	p.Asp65Ala	missense	Exon 1 of 7	NP_001345850.1
	COQ2	NM_015697.9		c.344A>C	p.Asp115Ala	missense	Exon 1 of 7	NP_056512.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ2	ENST00000647002.2	MANE Select	c.194A>C	p.Asp65Ala	missense	Exon 1 of 7	ENSP00000495761.2
	COQ2	ENST00000311469.9	TSL:1	c.344A>C	p.Asp115Ala	missense	Exon 1 of 7	ENSP00000310873.4
	COQ2	ENST00000311461.7	TSL:5	c.194A>C	p.Asp65Ala	missense	Exon 1 of 7	ENSP00000311835.7

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 807 AN: 151654 Hom.: 11 Cov.: 34

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000773 AC: 117 AN: 151298 AF XY: 0.000671

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000341

Gnomad OTH exome AF: 0.000245

GnomAD4 exome AF: 0.000460 AC: 647 AN: 1405640 Hom.: 4 Cov.: 84 AF XY: 0.000404 AC XY: 281 AN XY: 695252

African (AFR) AF: 0.0172 AC: 523 AN: 30376

American (AMR) AF: 0.000724 AC: 27 AN: 37288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24930

East Asian (EAS) AF: 0.00 AC: 0 AN: 35418

South Asian (SAS) AF: 0.0000626 AC: 5 AN: 79902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48388

Middle Eastern (MID) AF: 0.00182 AC: 10 AN: 5508

European-Non Finnish (NFE) AF: 0.0000157 AC: 17 AN: 1085666

Other (OTH) AF: 0.00112 AC: 65 AN: 58164

GnomAD4 genome AF: 0.00534 AC: 811 AN: 151770 Hom.: 11 Cov.: 34 AF XY: 0.00521 AC XY: 387 AN XY: 74222

African (AFR) AF: 0.0186 AC: 770 AN: 41392

American (AMR) AF: 0.00223 AC: 34 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10534

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67846

Other (OTH) AF: 0.00143 AC: 3 AN: 2102

Alfa AF: 0.00168 Hom.: 0

Bravo AF: 0.00620

ESP6500AA AF: 0.00876 AC: 25

ESP6500EA AF: 0.000150 AC: 1

ExAC AF: 0.000719 AC: 78

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	-	3	not provided (3)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	9.3
DANN	Benign	0.53
DEOGEN2	Benign	0.096	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.16
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.16
Sift	Benign	0.13	T
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.064
MVP		0.42
MPC		0.20
ClinPred		0.0054	T
GERP RS		-1.9
PromoterAI		0.083	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.38
Mutation Taster		=93/7	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: rs375934957; hg19: chr4-84205724; COSMIC: COSV107326993; COSMIC: COSV107326993;