rs149245323
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
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
NM_032609.3 missense
Scores
7
8
4
Clinical Significance
Conservation
PhyloP100: 3.49
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.41800255).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COX4I2 | NM_032609.3 | c.253C>T | p.Arg85Trp | missense_variant | 4/5 | ENST00000376075.4 | |
COX4I2 | XM_005260579.5 | c.268C>T | p.Arg90Trp | missense_variant | 3/4 | ||
COX4I2 | XM_005260580.5 | c.263-1359C>T | intron_variant | ||||
COX4I2 | XM_005260581.4 | c.248-1359C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COX4I2 | ENST00000376075.4 | c.253C>T | p.Arg85Trp | missense_variant | 4/5 | 1 | NM_032609.3 | P1 | |
COX4I2 | ENST00000490030.1 | n.278-1359C>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000486 AC: 74AN: 152224Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000529 AC: 133AN: 251486Hom.: 0 AF XY: 0.000618 AC XY: 84AN XY: 135922
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GnomAD4 exome AF: 0.000497 AC: 726AN: 1461764Hom.: 1 Cov.: 32 AF XY: 0.000529 AC XY: 385AN XY: 727166
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GnomAD4 genome ? AF: 0.000486 AC: 74AN: 152342Hom.: 0 Cov.: 32 AF XY: 0.000389 AC XY: 29AN XY: 74482
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 16, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at