NM_182476.3:c.1016A>G

Variant names:

• chr14-73961297-A-G
• rs2074930
• NM_182476.3:c.1016A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_182476.3(COQ6):​c.1016A>G​(p.Asp339Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D339V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COQ6 NM_182476.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.99
• Publications: 26 publications found

Genes affected

COQ6 (HGNC:20233): (coenzyme Q6, monooxygenase) The protein encoded by this gene belongs to the ubiH/COQ6 family. It is an evolutionarily conserved monooxygenase required for the biosynthesis of coenzyme Q10 (or ubiquinone), which is an essential component of the mitochondrial electron transport chain, and one of the most potent lipophilic antioxidants implicated in the protection of cell damage by reactive oxygen species. Knockdown of this gene in mouse and zebrafish results in decreased growth due to increased apoptosis. Mutations in this gene are associated with autosomal recessive coenzyme Q10 deficiency-6 (COQ10D6), which manifests as nephrotic syndrome with sensorineural deafness. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jun 2012]

ENTPD5 (HGNC:3367): (ectonucleoside triphosphate diphosphohydrolase 5 (inactive)) The protein encoded by this gene is similar to E-type nucleotidases (NTPases)/ecto-ATPase/apyrases. NTPases, such as CD39, mediate catabolism of extracellular nucleotides. ENTPD5 contains 4 apyrase-conserved regions which is characteristic of NTPases. [provided by RefSeq, Jan 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182476.3. 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
	COQ6	NM_182476.3	MANE Select	c.1016A>G	p.Asp339Gly	missense	Exon 9 of 12	NP_872282.1
	COQ6	NM_001425255.1		c.1016A>G	p.Asp339Gly	missense	Exon 9 of 11	NP_001412184.1
	COQ6	NM_182480.3		c.941A>G	p.Asp314Gly	missense	Exon 9 of 12	NP_872286.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ6	ENST00000334571.7	TSL:1 MANE Select	c.1016A>G	p.Asp339Gly	missense	Exon 9 of 12	ENSP00000333946.2
	COQ6	ENST00000554341.6	TSL:1	n.*621A>G		non_coding_transcript_exon	Exon 8 of 11	ENSP00000450736.2
	COQ6	ENST00000554341.6	TSL:1	n.*621A>G		3_prime_UTR	Exon 8 of 11	ENSP00000450736.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.047
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.0
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.058
Sift	Benign	0.38	T
Sift4G	Benign	0.42	T
Polyphen		0.0010	B
Vest4		0.20
MutPred		0.31		Gain of MoRF binding (P = 0.0287)
MVP		0.54
MPC		0.40
ClinPred		0.85	D
GERP RS		5.3
Varity_R		0.14
gMVP		0.73
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.94		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2074930; hg19: chr14-74428000;