rs6088858

Variant names:

• chr20-31639836-A-G
• rs6088858
• NM_032609.3:c.83-97A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032609.3(COX4I2):​c.83-97A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,385,560 control chromosomes in the GnomAD database, including 32,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6844 hom., cov: 31)
  • Exomes 𝑓: 0.19 (25680 hom.)
• Consequence: COX4I2 NM_032609.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.32
• Publications: 5 publications found

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]

COX4I2 Gene-Disease associations (from GenCC):

• pancreatic insufficiency-anemia-hyperostosis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 20-31639836-A-G is Benign according to our data. Variant chr20-31639836-A-G is described in ClinVar as Benign. ClinVar VariationId is 1229499.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032609.3. 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
	COX4I2	NM_032609.3	MANE Select	c.83-97A>G		intron	N/A	NP_115998.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX4I2	ENST00000376075.4	TSL:1 MANE Select	c.83-97A>G		intron	N/A	ENSP00000365243.3	Q96KJ9
	COX4I2	ENST00000948152.1		c.83-97A>G		intron	N/A	ENSP00000618211.1
	COX4I2	ENST00000890502.1		c.77-97A>G		intron	N/A	ENSP00000560561.1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40688 AN: 151782 Hom.: 6847 Cov.: 31

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0664

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.190 AC: 234818 AN: 1233660 Hom.: 25680 AF XY: 0.186 AC XY: 115731 AN XY: 621802

African (AFR) AF: 0.489 AC: 13898 AN: 28436

American (AMR) AF: 0.134 AC: 5390 AN: 40172

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 5434 AN: 24198

East Asian (EAS) AF: 0.000193 AC: 7 AN: 36240

South Asian (SAS) AF: 0.0680 AC: 5338 AN: 78518

European-Finnish (FIN) AF: 0.264 AC: 11756 AN: 44612

Middle Eastern (MID) AF: 0.156 AC: 658 AN: 4218

European-Non Finnish (NFE) AF: 0.197 AC: 181851 AN: 924718

Other (OTH) AF: 0.200 AC: 10486 AN: 52548

GnomAD4 genome AF: 0.268 AC: 40708 AN: 151900 Hom.: 6844 Cov.: 31 AF XY: 0.265 AC XY: 19701 AN XY: 74258

African (AFR) AF: 0.468 AC: 19376 AN: 41376

American (AMR) AF: 0.193 AC: 2939 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 813 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.0663 AC: 319 AN: 4814

European-Finnish (FIN) AF: 0.274 AC: 2887 AN: 10552

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13733 AN: 67932

Other (OTH) AF: 0.237 AC: 499 AN: 2104

Alfa AF: 0.258 Hom.: 768

Bravo AF: 0.275

Asia WGS AF: 0.0610 AC: 213 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.26
DANN	Benign	0.69
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs6088858; hg19: chr20-30227639;