rs61730662

chr16-57459717-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020312.4(COQ9):c.864G>C(p.Lys288Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 1,614,082 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (86 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (81 hom.)
• Consequence: COQ9 NM_020312.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.207

Genes affected

COQ9 (HGNC:25302): (coenzyme Q9) This locus represents a mitochondrial ubiquinone biosynthesis gene. The encoded protein is likely necessary for biosynthesis of coenzyme Q10, as mutations at this locus have been associated with autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency.[provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037902892).
• BP6: Variant 16-57459717-G-C is Benign according to our data. Variant chr16-57459717-G-C is described in ClinVar as [Benign]. Clinvar id is 136989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-57459717-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ9	NM_020312.4	c.864G>C	p.Lys288Asn	missense_variant	7/9	ENST00000262507.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ9	ENST00000262507.11	c.864G>C	p.Lys288Asn	missense_variant	7/9	1	NM_020312.4	P1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2622 AN: 152166 Hom.: 86 Cov.: 32

Gnomad AFR AF: 0.0602

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00430 AC: 1081 AN: 251176 Hom.: 38 AF XY: 0.00334 AC XY: 454 AN XY: 135756

Gnomad AFR exome AF: 0.0589

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00172 AC: 2512 AN: 1461798 Hom.: 81 Cov.: 32 AF XY: 0.00146 AC XY: 1061 AN XY: 727186

Gnomad4 AFR exome AF: 0.0611

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.0172 AC: 2625 AN: 152284 Hom.: 86 Cov.: 32 AF XY: 0.0169 AC XY: 1261 AN XY: 74472

Gnomad4 AFR AF: 0.0601

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00555 Hom.: 2

Bravo AF: 0.0189

ESP6500AA AF: 0.0573 AC: 252

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00525 AC: 637

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 28, 2015	- -

Encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 28, 2012

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.012	T;T;T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T;T;T;T
MetaRNN	Benign	0.0038	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.085
Sift	Benign	0.062	T;D;T;T
Sift4G	Benign	0.30	T;T;T;D
Polyphen		0.0050	B;.;.;.
Vest4		0.32
MutPred		0.45		Loss of ubiquitination at K288 (P = 0.0192);.;.;.;
MVP		0.42
MPC		0.20
ClinPred		0.020	T
GERP RS		1.1
Varity_R		0.21
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs61730662; hg19: chr16-57493629;