20-31640005-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032609.3(COX4I2):c.155C>A(p.Pro52His) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,272 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P52S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

COX4I2
NM_032609.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.96

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX4I2	NM_032609.3 link	c.155C>A	p.Pro52His	missense_variant	Exon 3 of 5	ENST00000376075.4	NP_115998.2	Q96KJ9H6SG14
COX4I2	XM_005260579.5 link	c.170C>A	p.Pro57His	missense_variant	Exon 2 of 4		XP_005260636.1
COX4I2	XM_005260580.5 link	c.170C>A	p.Pro57His	missense_variant	Exon 2 of 3		XP_005260637.1
COX4I2	XM_005260581.4 link	c.155C>A	p.Pro52His	missense_variant	Exon 3 of 4		XP_005260638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX4I2	ENST00000376075.4 link	c.155C>A	p.Pro52His	missense_variant	Exon 3 of 5	1	NM_032609.3	ENSP00000365243.3		Q96KJ9
COX4I2	ENST00000490030.1 link	n.185C>A		non_coding_transcript_exon_variant	Exon 3 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251160

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135742

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 52 of the COX4I2 protein (p.Pro52His). This variant is present in population databases (rs575560908, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with COX4I2-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.67

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.8

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.24

Sift

Uncertain

0.021

Sift4G

Uncertain

0.048

Polyphen

1.0

Vest4

0.65

MutPred

0.43

Loss of glycosylation at P52 (P = 0.0381);

MVP

0.81

MPC

0.63

ClinPred

0.92

GERP RS

3.8

Varity_R

0.67

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over