chr1-244835724-C-T

Variant names:

• chr1-244835724-C-T
• rs1330116844
• NM_198076.6:c.10C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198076.6(COX20):​c.10C>T​(p.Pro4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,268,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COX20 NM_198076.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.297
• 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: 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=0.04516819).

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.10C>T	p.Pro4Ser	missense	Exon 1 of 4	NP_932342.1	Q5RI15-1
	COX20	NM_001312872.1		c.10C>T	p.Pro4Ser	missense	Exon 1 of 5	NP_001299801.1	B3KM21
	COX20	NM_001312871.1		c.10C>T	p.Pro4Ser	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.10C>T	p.Pro4Ser	missense	Exon 1 of 4	ENSP00000406327.2	Q5RI15-1
	COX20	ENST00000391839.6	TSL:1	n.69C>T		non_coding_transcript_exon	Exon 1 of 3
	COX20	ENST00000366528.3	TSL:2	c.10C>T	p.Pro4Ser	missense	Exon 1 of 5	ENSP00000355486.3	Q5RI15-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151956 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000269 AC: 3 AN: 1116792 Hom.: 0 Cov.: 31 AF XY: 0.00000561 AC XY: 3 AN XY: 534530

African (AFR) AF: 0.00 AC: 0 AN: 23534

American (AMR) AF: 0.00 AC: 0 AN: 10932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15636

East Asian (EAS) AF: 0.0000371 AC: 1 AN: 26918

South Asian (SAS) AF: 0.00 AC: 0 AN: 30098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3412

European-Non Finnish (NFE) AF: 0.00000214 AC: 2 AN: 936662

Other (OTH) AF: 0.00 AC: 0 AN: 44928

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151956 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74222

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.0000655 AC: 1 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Mitochondrial complex IV deficiency, nuclear type 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.8
DANN	Benign	0.95
DEOGEN2	Benign	0.087	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.30
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.030
Sift	Benign	0.45	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.063
MutPred		0.25		Loss of catalytic residue at P4 (P = 1e-04)
MVP		0.048
MPC		0.030
ClinPred		0.051	T
GERP RS		3.3
PromoterAI		0.053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.023
gMVP		0.11
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1330116844; hg19: chr1-244999026;