14-73958229-G-C

Variant names:

• chr14-73958229-G-C
• rs1057519349
• NM_182476.3:c.564G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_182476.3(COQ6):​c.564G>C​(p.Trp188Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COQ6 NM_182476.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.46
• Publications: 3 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ6	NM_182476.3	c.564G>C	p.Trp188Cys	missense_variant	Exon 5 of 12	ENST00000334571.7	NP_872282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COQ6	ENST00000334571.7	c.564G>C	p.Trp188Cys	missense_variant	Exon 5 of 12	1	NM_182476.3	ENSP00000333946.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;T;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.4	.;.;M;.
PhyloP100		8.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.0	D;.;D;D
REVEL	Uncertain	0.42
Sift	Benign	0.049	D;.;D;D
Sift4G	Benign	0.099	T;T;T;T
Polyphen		1.0	.;.;D;D
Vest4		0.90
MutPred		0.40		.;.;Gain of catalytic residue at P187 (P = 0.0103);.;
MVP		0.82
MPC		1.2
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.59
gMVP		0.85
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1057519349; hg19: chr14-74424932;