rs121918232

Variant names:

• chr4-83273505-T-C
• rs121918232
• NM_001358921.2:c.533A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PP3_Moderate PP5 BS1_Supporting

The NM_001358921.2(COQ2):​c.533A>G​(p.Asn178Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,613,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: COQ2 NM_001358921.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2 O:1
• Conservation: PhyloP100: 7.70
• Publications: 23 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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852
• PP5: Variant 4-83273505-T-C is Pathogenic according to our data. Variant chr4-83273505-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1439.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00019 (278/1460790) while in subpopulation NFE AF = 0.000244 (271/1111494). AF 95% confidence interval is 0.00022. There are 0 homozygotes in GnomAdExome4. There are 137 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ2	NM_001358921.2	c.533A>G	p.Asn178Ser	missense_variant	Exon 3 of 7	ENST00000647002.2	NP_001345850.1
COQ2	NM_015697.9	c.683A>G	p.Asn228Ser	missense_variant	Exon 3 of 7		NP_056512.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COQ2	ENST00000647002.2	c.533A>G	p.Asn178Ser	missense_variant	Exon 3 of 7		NM_001358921.2	ENSP00000495761.2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152222 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000125 AC: 31 AN: 248218 AF XY: 0.000111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000258

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000190 AC: 278 AN: 1460790 Hom.: 0 Cov.: 30 AF XY: 0.000189 AC XY: 137 AN XY: 726662

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86064

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000244 AC: 271 AN: 1111494

Other (OTH) AF: 0.0000994 AC: 6 AN: 60340

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152222 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74368

African (AFR) AF: 0.0000724 AC: 3 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000163 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.000166 AC: 20

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Coenzyme Q10 deficiency, primary, 1 Pathogenic:2 Uncertain:1

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Asn228Ser variant in COQ2 was identified by our study in the compound heterozygous state, along with another VUS, in one individual with primary coenzyme q10 deficiency. The p.Asn228Ser variant in COQ2 has been reported in 1 Eastern European individual withprimary coenzyme q10 deficiency (PMID: 17855635), and has been identified in 0.02376% (30/126254) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121918232). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The presence of this variant in combination with a variant reported pathogenic by OMIM in ClinVar and in an individual with primary coenzyme q10 deficiency slightly increases the likelihood that the p.Asn228Ser variant is pathogenic (PMID: 17855635; Variation ID: 1438). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PM3_Supporting (Richards 2015). -

Oct 07, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COQ2 c.683A>G (p.Asn228Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 248218 control chromosomes. This frequency does not allow conclusions about variant significance. c.683A>G has been reported in the literature as biallelic compound heterozygous or homozygous genotypes in multiple comprehensively genotyped (WES or large NGS panel based analysis) individuals affected with Coenzyme Q10 Deficiency, Primary, 1 (example, Dimedl-Camassei_2007, McCarthy_2013, Sadowski_2015, Shapiro_2019, Warejko_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported although individuals with compound heterozygous genotypes have been reported with biochemical analyses demonstrating decreased activities of respiratory chain complexes (II + III) and decreased CoQ10 levels in the skeletal muscle and renal cortex, findings consistent with the pathophysiology of disease (Dimedl-Camassei_2007, Lopez_2010). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=2; Likely pathogenic, n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1 Uncertain:1

Jun 28, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed multiple times with another COQ2 variant in patients with childhood-onset renal disease in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 29127259, 29637272, 30295827); Published functional studies in yeast suggest a damaging effect: decreased CoQ content compared to wild type (PMID: 27493029); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20495179, 25373618, 31660881, 30295827, 29127259, 29637272, 33426503, 23343605, 27493029, 17855635, 18235438, 23349334, 36420660, 20689595, 35483523, 36266294, 29869118, 38774208, 37734845) -

Aug 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 228 of the COQ2 protein (p.Asn228Ser). This variant is present in population databases (rs121918232, gnomAD 0.02%). This missense change has been observed in individual(s) with COQ2-related steroid-resistant nephrotic syndrome (PMID: 17855635, 23349334, 29127259, 29637272, 29869118, 30295827). ClinVar contains an entry for this variant (Variation ID: 1439). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects COQ2 function (PMID: 17855635, 20689595). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Pathogenic:1

Apr 15, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.683A>G (p.N228S) alteration is located in exon 3 (coding exon 3) of the COQ2 gene. This alteration results from an A to G substitution at nucleotide position 683, causing the asparagine (N) at amino acid position 228 to be replaced by a serine (S). Based on data from the Genome Aggregation Database (gnomAD) database, the COQ2 c.683A>G alteration was observed in 0.01% (32/279612) of total alleles studied, with a frequency of 0.02% (29/127994) in the non-Finnish European subpopulation. This alteration has been reported in the homozygous or compound heterozygous state with other COQ2 variants in multiple individuals with steroid-resistant nephrotic syndrome (Diomedi-Camassei, 2007; McCarthy, 2013; Sadowski, 2015; Bezdíka, 2018; Warejko, 2018; Starr, 2018; Schapiro, 2019). This amino acid position is completely conserved on sequence alignment. Studies of patient skin fibroblasts with this alteration showed decreased CoQ10 levels, decreased ATP, increased protein oxidation, and cell death, while studies in a yeast model demonstrated decreased CoQ6 production (described as N178S/p.Asn178Ser due to alternate nomenclature) (Quinzii, 2010; Desbats, 2016). The in silico prediction for the p.N228S alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Nephrotic syndrome Pathogenic:1

Nov 10, 2017

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Coenzyme Q10 deficiency Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.0096	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	.;.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Pathogenic	0.98	D
PhyloP100		7.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.9	.;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	.;D;D
Sift4G	Uncertain	0.0080	.;D;D
Polyphen		0.75	.;.;P
Vest4		0.98, 0.98
MVP		0.99
MPC		0.29
ClinPred		0.45	T
GERP RS		5.6
gMVP		0.73
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121918232; hg19: chr4-84194658;