rs375934957

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-83284571-T-A
• chr4-83284571-T-C
• chr4-83284571-T-G

Variant summary

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

The ENST00000647002.2(COQ2):​c.194A>T​(p.Asp65Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,405,644 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D65A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: COQ2 ENST00000647002.2 missense
• Clinical Significance: Not reported in ClinVar
• 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: 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=0.07726097).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000647002.2. 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>T	p.Asp65Val	missense	Exon 1 of 7	NP_001345850.1
	COQ2	NM_015697.9		c.344A>T	p.Asp115Val	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>T	p.Asp65Val	missense	Exon 1 of 7	ENSP00000495761.2
	COQ2	ENST00000311469.9	TSL:1	c.344A>T	p.Asp115Val	missense	Exon 1 of 7	ENSP00000310873.4
	COQ2	ENST00000311461.7	TSL:5	c.194A>T	p.Asp65Val	missense	Exon 1 of 7	ENSP00000311835.7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1405644 Hom.: 0 Cov.: 84 AF XY: 0.00 AC XY: 0 AN XY: 695256

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30380

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 79902

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5508

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085666

Other (OTH) AF: 0.0000172 AC: 1 AN: 58164

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.61
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.16
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.19
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.020	D
Polyphen		0.014	B
Vest4		0.21
MutPred		0.45		Loss of glycosylation at P70 (P = 0.0216)
MVP		0.55
MPC		0.27
ClinPred		0.22	T
GERP RS		-1.9
PromoterAI		-0.081	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.48
Mutation Taster		=95/5	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;