chr20-31643409-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_032609.3(COX4I2):c.253C>T(p.Arg85Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,614,106 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 1 hom. )

Consequence

COX4I2
NM_032609.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.49

Publications

3 publications found

Variant links:

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

COX4I2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.41800255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COX4I2	NM_032609.3 link	c.253C>T	p.Arg85Trp	missense_variant	Exon 4 of 5	ENST00000376075.4	NP_115998.2
COX4I2	XM_005260579.5 link	c.268C>T	p.Arg90Trp	missense_variant	Exon 3 of 4		XP_005260636.1
COX4I2	XM_005260580.5 link	c.263-1359C>T		intron_variant	Intron 2 of 2		XP_005260637.1
COX4I2	XM_005260581.4 link	c.248-1359C>T		intron_variant	Intron 3 of 3		XP_005260638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX4I2	ENST00000376075.4 link	c.253C>T	p.Arg85Trp	missense_variant	Exon 4 of 5	1	NM_032609.3	ENSP00000365243.3
COX4I2	ENST00000490030.1 link	n.278-1359C>T		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000529

AC:

133

AN:

251486

AF XY:

0.000618

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.000694

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000791

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000497

AC:

726

AN:

1461764

Hom.:

Cov.:

AF XY:

0.000529

AC XY:

385

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000514

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000689

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.000603

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00402

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.000512

AC:

569

AN:

1111986

Other (OTH)

AF:

0.000629

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

AF:

0.000486

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41590

American (AMR)

AF:

0.000523

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000676

Hom.:

Bravo

AF:

0.000529

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000502

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00166

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Oct 16, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 85 of the COX4I2 protein (p.Arg85Trp). This variant is present in population databases (rs149245323, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with COX4I2-related conditions. ClinVar contains an entry for this variant (Variation ID: 197362). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dec 07, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.42

MetaSVM

Uncertain

-0.28

MutationAssessor

Pathogenic

3.5

PhyloP100

3.5

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.5

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.78

MVP

0.87

MPC

0.60

ClinPred

0.25

GERP RS

4.0

Varity_R

0.90

gMVP

0.83

Mutation Taster

=36/64

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over