Genetic Variant NM_198076.6:c.13C>A (chr1-244835727-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_198076.6(COX20):c.13C>A(p.Pro5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000894 in 1,118,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. P5S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.9e-7 ( 0 hom. )

Consequence

COX20
NM_198076.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.213

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a chain Cytochrome c oxidase assembly protein COX20, mitochondrial (size 116) in uniprot entity COX20_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_198076.6

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052765757).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX20	NM_198076.6 link	c.13C>A	p.Pro5Thr	missense_variant	Exon 1 of 4	ENST00000411948.7	NP_932342.1	Q5RI15-1B3KM21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COX20	ENST00000411948.7 link	c.13C>A	p.Pro5Thr	missense_variant	Exon 1 of 4	1	NM_198076.6	ENSP00000406327.2	Q5RI15-1
COX20	ENST00000391839.6 link	n.72C>A		non_coding_transcript_exon_variant	Exon 1 of 3	1
COX20	ENST00000366528.3 link	c.13C>A	p.Pro5Thr	missense_variant	Exon 1 of 5	2		ENSP00000355486.3	Q5RI15-2
COX20	ENST00000498262.1 link	n.69C>A		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.94e-7

AC:

AN:

1118024

Hom.:

Cov.:

AF XY:

0.00000187

AC XY:

AN XY:

535228

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:

0.0000330

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

6.1

DANN

Uncertain

0.97

DEOGEN2

Benign

0.097

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.56

T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.24

N;N

REVEL

Benign

0.042

Sift

Benign

0.62

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.0010

B;.

Vest4

0.12

MutPred

0.21

Gain of phosphorylation at P5 (P = 0.0106);Gain of phosphorylation at P5 (P = 0.0106);

MVP

0.081

MPC

0.032

ClinPred

0.061

GERP RS

0.44

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.065

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over