1-244835736-G-A

Position:

• chr1-244835736-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_198076.6(COX20):​c.22G>A​(p.Gly8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000178 in 1,122,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G8G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: COX20 NM_198076.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.569

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]

ACMG classification

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 7 pathogenic changes around while only 2 benign (78%) in NM_198076.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048508704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX20	NM_198076.6	c.22G>A	p.Gly8Ser	missense_variant	1/4	ENST00000411948.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COX20	ENST00000411948.7	c.22G>A	p.Gly8Ser	missense_variant	1/4	1	NM_198076.6	P1
COX20	ENST00000391839.6	n.81G>A		non_coding_transcript_exon_variant	1/3	1
COX20	ENST00000366528.3	c.22G>A	p.Gly8Ser	missense_variant	1/5	2
COX20	ENST00000498262.1	n.78G>A		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000178 AC: 2 AN: 1122514 Hom.: 0 Cov.: 31 AF XY: 0.00000186 AC XY: 1 AN XY: 537910

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000170

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 8 of the COX20 protein (p.Gly8Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COX20-related conditions. ClinVar contains an entry for this variant (Variation ID: 1472963). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.0
DANN	Uncertain	0.99
DEOGEN2	Benign	0.081	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.38	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.11	N;N
REVEL	Benign	0.011
Sift	Benign	0.37	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0030	B;.
Vest4		0.12
MutPred		0.20		Gain of phosphorylation at G8 (P = 0.0022);Gain of phosphorylation at G8 (P = 0.0022);
MVP		0.030
MPC		0.033
ClinPred		0.072	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs961642913; hg19: chr1-244999038;