4-73064835-G-A

Position:

• chr4-73064835-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001297732.2(COX18):​c.666C>T​(p.Pro222Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,612,634 control chromosomes in the GnomAD database, including 146,648 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.36 (10562 hom., cov: 33)
  • Exomes 𝑓: 0.43 (136086 hom.)
• Consequence: COX18 NM_001297732.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0820

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP7: Synonymous conserved (PhyloP=-0.082 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX18	NM_001297732.2	c.666C>T	p.Pro222Pro	synonymous_variant	4/6	ENST00000507544.3	NP_001284661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX18	ENST00000507544.3	c.666C>T	p.Pro222Pro	synonymous_variant	4/6	1	NM_001297732.2	ENSP00000425261.3

Frequencies

GnomAD3 genomes AF: 0.362 AC: 55068 AN: 151930 Hom.: 10561 Cov.: 33

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.347

GnomAD3 exomes AF: 0.391 AC: 98215 AN: 251342 Hom.: 20256 AF XY: 0.402 AC XY: 54680 AN XY: 135868

Gnomad AFR exome AF: 0.228

Gnomad AMR exome AF: 0.265

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.384

Gnomad SAS exome AF: 0.452

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.437

Gnomad OTH exome AF: 0.411

GnomAD4 exome AF: 0.427 AC: 624207 AN: 1460586 Hom.: 136086 Cov.: 34 AF XY: 0.429 AC XY: 311691 AN XY: 726650

Gnomad4 AFR exome AF: 0.221

Gnomad4 AMR exome AF: 0.270

Gnomad4 ASJ exome AF: 0.357

Gnomad4 EAS exome AF: 0.353

Gnomad4 SAS exome AF: 0.456

Gnomad4 FIN exome AF: 0.409

Gnomad4 NFE exome AF: 0.444

Gnomad4 OTH exome AF: 0.405

GnomAD4 genome AF: 0.362 AC: 55075 AN: 152048 Hom.: 10562 Cov.: 33 AF XY: 0.359 AC XY: 26675 AN XY: 74320

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.312

Gnomad4 ASJ AF: 0.349

Gnomad4 EAS AF: 0.373

Gnomad4 SAS AF: 0.455

Gnomad4 FIN AF: 0.397

Gnomad4 NFE AF: 0.441

Gnomad4 OTH AF: 0.343

Alfa AF: 0.407 Hom.: 14829

Bravo AF: 0.347

EpiCase AF: 0.437

EpiControl AF: 0.439

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.4
DANN	Benign	0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs3762883; hg19: chr4-73930552; COSMIC: COSV55720371; COSMIC: COSV55720371;