chr1-244835722-C-G

Variant names:

• chr1-244835722-C-G
• rs1679951764
• NM_198076.6:c.8C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198076.6(COX20):​c.8C>G​(p.Ala3Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000896 in 1,116,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. A3T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.0e-7 (0 hom.)
• Consequence: COX20 NM_198076.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.24
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08420783).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX20	NM_198076.6	MANE Select	c.8C>G	p.Ala3Gly	missense	Exon 1 of 4	NP_932342.1	Q5RI15-1
	COX20	NM_001312872.1		c.8C>G	p.Ala3Gly	missense	Exon 1 of 5	NP_001299801.1	B3KM21
	COX20	NM_001312871.1		c.8C>G	p.Ala3Gly	missense	Exon 2 of 5	NP_001299800.1	Q5RI15-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX20	ENST00000411948.7	TSL:1 MANE Select	c.8C>G	p.Ala3Gly	missense	Exon 1 of 4	ENSP00000406327.2	Q5RI15-1
	COX20	ENST00000391839.6	TSL:1	n.67C>G		non_coding_transcript_exon	Exon 1 of 3
	COX20	ENST00000366528.3	TSL:2	c.8C>G	p.Ala3Gly	missense	Exon 1 of 5	ENSP00000355486.3	Q5RI15-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.96e-7 AC: 1 AN: 1116624 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 534512

African (AFR) AF: 0.00 AC: 0 AN: 23528

American (AMR) AF: 0.00 AC: 0 AN: 10942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15644

East Asian (EAS) AF: 0.00 AC: 0 AN: 26932

South Asian (SAS) AF: 0.00 AC: 0 AN: 30054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3346

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 936654

Other (OTH) AF: 0.00 AC: 0 AN: 44938

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.46	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.11
Sift	Uncertain	0.027	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.29	B
Vest4		0.13
MutPred		0.26		Loss of stability (P = 0.043)
MVP		0.030
MPC		0.039
ClinPred		0.88	D
GERP RS		4.3
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.17
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1679951764; hg19: chr1-244999024;