Genetic Variant COX20:p.Pro4Ala (chr1-244835724-C-G) – 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.10C>G(p.Pro4Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

COX20
NM_198076.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.297

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:

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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=0.034888715).

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.10C>G	p.Pro4Ala	missense	Exon 1 of 4	NP_932342.1	Q5RI15-1
COX20	NM_001312872.1		c.10C>G	p.Pro4Ala	missense	Exon 1 of 5	NP_001299801.1	B3KM21
COX20	NM_001312871.1		c.10C>G	p.Pro4Ala	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.10C>G	p.Pro4Ala	missense	Exon 1 of 4	ENSP00000406327.2	Q5RI15-1
COX20	ENST00000391839.6	TSL:1	n.69C>G		non_coding_transcript_exon	Exon 1 of 3
COX20	ENST00000366528.3	TSL:2	c.10C>G	p.Pro4Ala	missense	Exon 1 of 5	ENSP00000355486.3	Q5RI15-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

1.0

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.087

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00057

LIST_S2

Benign

0.27

M_CAP

Benign

0.034

MetaRNN

Benign

0.035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

PhyloP100

0.30

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.92

REVEL

Benign

0.056

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.086

MutPred

0.27

Loss of catalytic residue at P4 (P = 0.0064)

MVP

0.048

MPC

0.029

ClinPred

0.050

GERP RS

3.3

PromoterAI

0.11

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.023

gMVP

0.084

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over