Genetic Variant COX20:p.Pro5Ser (chr1-244835727-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_198076.6(COX20):c.13C>T(p.Pro5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000268 in 1,118,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

COX20
NM_198076.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.213

Publications

0 publications found

Variant links:

Genes affected

COX20 (HGNC:26970): (cytochrome c oxidase assembly factor COX20) This gene encodes a protein that plays a role in the assembly of cytochrome C oxidase, an important component of the respiratory pathway. It contains two transmembrane helices and localizes to the mitochondrial membrane. Mutations in this gene can cause mitochondrial complex IV deficiency, which results in ataxia and muscle hypotonia. There are multiple pseudogenes for this gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

COX20 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial complex IV deficiency, nuclear type 11
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
cytochrome-c oxidase deficiency disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

COX20 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.059129745).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198076.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COX20	NM_198076.6	MANE Select	c.13C>T	p.Pro5Ser	missense	Exon 1 of 4	NP_932342.1	Q5RI15-1
COX20	NM_001312872.1		c.13C>T	p.Pro5Ser	missense	Exon 1 of 5	NP_001299801.1	B3KM21
COX20	NM_001312871.1		c.13C>T	p.Pro5Ser	missense	Exon 2 of 5	NP_001299800.1	Q5RI15-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COX20	ENST00000411948.7	TSL:1 MANE Select	c.13C>T	p.Pro5Ser	missense	Exon 1 of 4	ENSP00000406327.2	Q5RI15-1
COX20	ENST00000391839.6	TSL:1	n.72C>T		non_coding_transcript_exon	Exon 1 of 3
COX20	ENST00000366528.3	TSL:2	c.13C>T	p.Pro5Ser	missense	Exon 1 of 5	ENSP00000355486.3	Q5RI15-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000268

AC:

AN:

1118022

Hom.:

Cov.:

AF XY:

0.00000187

AC XY:

AN XY:

535226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23556

American (AMR)

AF:

0.0000903

AC:

AN:

11080

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15704

East Asian (EAS)

AF:

0.00

AC:

AN:

26936

South Asian (SAS)

AF:

0.00

AC:

AN:

30346

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3442

European-Non Finnish (NFE)

AF:

0.00000213

AC:

AN:

937046

Other (OTH)

AF:

0.00

AC:

AN:

44976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

5.0

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.097

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.56

M_CAP

Benign

0.040

MetaRNN

Benign

0.059

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

-0.21

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.19

REVEL

Benign

0.038

Sift

Benign

0.48

Sift4G

Benign

0.19

Polyphen

0.0020

Vest4

0.12

MutPred

0.21

Gain of phosphorylation at P5 (P = 0.006)

MVP

0.048

MPC

0.035

ClinPred

0.065

GERP RS

0.44

PromoterAI

-0.035

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.038

gMVP

0.23

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over