rs114521946

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001303.4(COX10):c.682C>T(p.Arg228Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,612,150 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R228H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0067 ( 10 hom., cov: 33)

Exomes 𝑓: 0.00072 ( 12 hom. )

Consequence

COX10
NM_001303.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.88

Publications

4 publications found

Variant links:

Genes affected

COX10 (HGNC:2260): (cytochrome c oxidase assembly factor heme A:farnesyltransferase COX10) Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene encodes heme A:farnesyltransferase, which is not a structural subunit but required for the expression of functional COX and functions in the maturation of the heme A prosthetic group of COX. This protein is predicted to contain 7-9 transmembrane domains localized in the mitochondrial inner membrane. A gene mutation, which results in the substitution of a lysine for an asparagine (N204K), is identified to be responsible for cytochrome c oxidase deficiency. In addition, this gene is disrupted in patients with CMT1A (Charcot-Marie-Tooth type 1A) duplication and with HNPP (hereditary neuropathy with liability to pressure palsies) deletion. [provided by RefSeq, Jul 2008]

COX10 Gene-Disease associations (from GenCC):

mitochondrial complex IV deficiency, nuclear type 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
cytochrome-c oxidase deficiency disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

COX10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001303.4

BP4

Computational evidence support a benign effect (MetaRNN=0.018391252).

BP6

Variant 17-14159934-C-T is Benign according to our data. Variant chr17-14159934-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137010.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0067 (1019/152200) while in subpopulation AFR AF = 0.0231 (961/41526). AF 95% confidence interval is 0.0219. There are 10 homozygotes in GnomAd4. There are 460 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX10	NM_001303.4 link	c.682C>T	p.Arg228Cys	missense_variant	Exon 5 of 7	ENST00000261643.8	NP_001294.2	Q12887-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX10	ENST00000261643.8 link	c.682C>T	p.Arg228Cys	missense_variant	Exon 5 of 7	1	NM_001303.4	ENSP00000261643.3		Q12887-1

Frequencies

GnomAD3 genomes

AF:

0.00667

AC:

1015

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0231

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00184

AC:

459

AN:

249804

AF XY:

0.00136

show subpopulations

Gnomad AFR exome

AF:

0.0247

Gnomad AMR exome

AF:

0.000813

Gnomad ASJ exome

AF:

0.00170

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000974

Gnomad OTH exome

AF:

0.000656

GnomAD4 exome

AF:

0.000717

AC:

1047

AN:

1459950

Hom.:

Cov.:

AF XY:

0.000614

AC XY:

446

AN XY:

726206

show subpopulations

African (AFR)

AF:

0.0232

AC:

774

AN:

33434

American (AMR)

AF:

0.00110

AC:

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.00146

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.0000349

AC:

AN:

86000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.000588

AC:

AN:

5104

European-Non Finnish (NFE)

AF:

0.0000864

AC:

AN:

1111400

Other (OTH)

AF:

0.00139

AC:

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00670

AC:

1019

AN:

152200

Hom.:

Cov.:

AF XY:

0.00618

AC XY:

460

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0231

AC:

961

AN:

41526

American (AMR)

AF:

0.00223

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

105

157

210

262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00222

Hom.:

Bravo

AF:

0.00752

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0252

AC:

111

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00245

AC:

297

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 19, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 17, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mitochondrial complex IV deficiency, nuclear type 1

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Apr 25, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Leigh syndrome

Benign:1

Jul 08, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.018

MetaSVM

Uncertain

0.43

MutationAssessor

Uncertain

2.9

PhyloP100

2.9

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.73

Sift

Uncertain

0.019

Sift4G

Uncertain

0.027

Polyphen

0.94

Vest4

0.65

MVP

0.71

MPC

1.1

ClinPred

0.065

GERP RS

5.0

Varity_R

0.58

gMVP

0.81

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over