20-31638887-G-A

Position:

• chr20-31638887-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032609.3(COX4I2):​c.1-131G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 965,866 control chromosomes in the GnomAD database, including 23,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6860 hom., cov: 31)
  • Exomes 𝑓: 0.19 (16895 hom.)
• Consequence: COX4I2 NM_032609.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0130

Genes affected

COX4I2 (HGNC:16232): (cytochrome c oxidase subunit 4I2) Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes isoform 2 of subunit IV. Isoform 1 of subunit IV is encoded by a different gene, however, the two genes show a similar structural organization. Subunit IV is the largest nuclear encoded subunit which plays a pivotal role in COX regulation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 20-31638887-G-A is Benign according to our data. Variant chr20-31638887-G-A is described in ClinVar as [Benign]. Clinvar id is 1267585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX4I2	NM_032609.3	c.1-131G>A		intron_variant		ENST00000376075.4	NP_115998.2
COX4I2	XM_005260581.4	c.1-131G>A		intron_variant			XP_005260638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX4I2	ENST00000376075.4	c.1-131G>A		intron_variant		1	NM_032609.3	ENSP00000365243	P1
COX4I2	ENST00000490030.1	n.31-131G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40767 AN: 151954 Hom.: 6863 Cov.: 31

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.0664

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.239

GnomAD4 exome AF: 0.189 AC: 153538 AN: 813794 Hom.: 16895 AF XY: 0.182 AC XY: 76614 AN XY: 420110

Gnomad4 AFR exome AF: 0.481

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.223

Gnomad4 EAS exome AF: 0.000183

Gnomad4 SAS exome AF: 0.0689

Gnomad4 FIN exome AF: 0.264

Gnomad4 NFE exome AF: 0.198

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.268 AC: 40787 AN: 152072 Hom.: 6860 Cov.: 31 AF XY: 0.265 AC XY: 19736 AN XY: 74352

Gnomad4 AFR AF: 0.468

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.000583

Gnomad4 SAS AF: 0.0663

Gnomad4 FIN AF: 0.274

Gnomad4 NFE AF: 0.202

Gnomad4 OTH AF: 0.237

Alfa AF: 0.225 Hom.: 883

Bravo AF: 0.275

Asia WGS AF: 0.0610 AC: 213 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.0
DANN	Benign	0.89

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

LitVar

Other links and lift over

dbSNP: rs45557936; hg19: chr20-30226690;