NM_001297732.2:c.785G>C

Variant names:

• chr4-73061859-C-G
• rs370963998
• NM_001297732.2:c.785G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001297732.2(COX18):​c.785G>C​(p.Arg262Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R262L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COX18 NM_001297732.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.89
• Publications: 0 publications found

Genes affected

COX18 (HGNC:26801): (cytochrome c oxidase assembly factor COX18) This gene encodes a cytochrome c oxidase assembly protein. The encoded protein is essential for integral membrane protein insertion into the mitochondrial inner membrane. It is also required for cytochrome c oxidase assembly and activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001297732.2. 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
	COX18	NM_001297732.2	MANE Select	c.785G>C	p.Arg262Pro	missense	Exon 5 of 6	NP_001284661.1	B7ZL88
	COX18	NM_001300729.1		c.791G>C	p.Arg264Pro	missense	Exon 4 of 5	NP_001287658.1	Q8N8Q8
	COX18	NM_173827.4		c.782G>C	p.Arg261Pro	missense	Exon 5 of 6	NP_776188.1	Q8N8Q8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX18	ENST00000507544.3	TSL:1 MANE Select	c.785G>C	p.Arg262Pro	missense	Exon 5 of 6	ENSP00000425261.3	B7ZL88
	COX18	ENST00000295890.8	TSL:1	c.782G>C	p.Arg261Pro	missense	Exon 5 of 6	ENSP00000295890.4	Q8N8Q8-1
	COX18	ENST00000449739.6	TSL:1	n.*291G>C		non_coding_transcript_exon	Exon 4 of 5	ENSP00000394583.2	Q8N8Q8-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.98	D
Vest4		0.98
MutPred		0.81		Loss of methylation at R262 (P = 0.0038)
MVP		0.46
MPC		1.2
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.97
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs370963998; hg19: chr4-73927576;