chr4-83273505-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2PP3_ModeratePP5BS1_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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2O:1

Conservation

PhyloP100: 7.70

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 1439.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2, Pathogenic=1, not_provided=1}. Variant chr4-83273505-T-C is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 137 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. 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 link	c.533A>G	p.Asn178Ser	missense_variant	Exon 3 of 7	ENST00000647002.2	NP_001345850.1
COQ2	NM_015697.9 link	c.683A>G	p.Asn228Ser	missense_variant	Exon 3 of 7		NP_056512.5	Q96H96-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COQ2	ENST00000647002.2 link	c.533A>G	p.Asn178Ser	missense_variant	Exon 3 of 7		NM_001358921.2	ENSP00000495761.2		Q96H96-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000125

AC:

AN:

248218

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

134644

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000189

AC XY:

137

AN XY:

726662

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000244

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000190

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.000166

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Coenzyme Q10 deficiency, primary, 1

Pathogenic:2Uncertain:1

Oct 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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. -

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). -

not provided

Pathogenic:1Uncertain:1

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. -

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) -

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

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

.;.;D

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

D;.;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Pathogenic

0.98

PrimateAI

Uncertain

0.67

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

GERP RS

5.6

gMVP

0.73

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over