Genetic Variant COX18:p.Ala92Thr (chr4-73069376-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001300729.1(COX18):c.384G>A(p.Trp128*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,407,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

COX18
NM_001300729.1 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.12

Publications

0 publications found

Variant links:

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]

COX18 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001300729.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COX18	NM_001297732.2	MANE Select	c.274G>A	p.Ala92Thr	missense	Exon 1 of 6	NP_001284661.1	B7ZL88
COX18	NM_001300729.1		c.384G>A	p.Trp128*	stop_gained	Exon 1 of 5	NP_001287658.1	Q8N8Q8
COX18	NM_173827.4		c.274G>A	p.Ala92Thr	missense	Exon 1 of 6	NP_776188.1	Q8N8Q8-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COX18	ENST00000507544.3	TSL:1 MANE Select	c.274G>A	p.Ala92Thr	missense	Exon 1 of 6	ENSP00000425261.3	B7ZL88
COX18	ENST00000295890.8	TSL:1	c.274G>A	p.Ala92Thr	missense	Exon 1 of 6	ENSP00000295890.4	Q8N8Q8-1
COX18	ENST00000421792.2	TSL:1	n.380G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.11e-7

AC:

AN:

1407414

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

695390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32192

American (AMR)

AF:

0.00

AC:

AN:

37114

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25246

East Asian (EAS)

AF:

0.00

AC:

AN:

36638

South Asian (SAS)

AF:

0.00

AC:

AN:

80110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4534

European-Non Finnish (NFE)

AF:

9.22e-7

AC:

AN:

1084850

Other (OTH)

AF:

0.00

AC:

AN:

58276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.61

M_CAP

Benign

0.011

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.95

PhyloP100

1.1

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.3

REVEL

Benign

0.13

Sift

Benign

0.27

Sift4G

Benign

0.46

Polyphen

0.012

Vest4

0.23

MutPred

0.34

Loss of glycosylation at S89 (P = 0.0355)

MVP

0.10

MPC

0.31

ClinPred

0.24

GERP RS

4.0

PromoterAI

0.040

Neutral

(source)

Varity_R

0.19

gMVP

0.43

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over