20-31644800-G-A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_032609.3(COX4I2):c.412G>A(p.Glu138Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000394 in 1,614,062 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_032609.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COX4I2 | NM_032609.3 | c.412G>A | p.Glu138Lys | missense_variant | Exon 5 of 5 | ENST00000376075.4 | NP_115998.2 | |
COX4I2 | XM_005260579.5 | c.427G>A | p.Glu143Lys | missense_variant | Exon 4 of 4 | XP_005260636.1 | ||
COX4I2 | XM_005260580.5 | c.295G>A | p.Glu99Lys | missense_variant | Exon 3 of 3 | XP_005260637.1 | ||
COX4I2 | XM_005260581.4 | c.280G>A | p.Glu94Lys | missense_variant | Exon 4 of 4 | XP_005260638.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00203 AC: 309AN: 152092Hom.: 2 Cov.: 31
GnomAD3 exomes AF: 0.000513 AC: 129AN: 251238Hom.: 1 AF XY: 0.000449 AC XY: 61AN XY: 135834
GnomAD4 exome AF: 0.000223 AC: 326AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.000216 AC XY: 157AN XY: 727230
GnomAD4 genome AF: 0.00204 AC: 310AN: 152210Hom.: 2 Cov.: 31 AF XY: 0.00199 AC XY: 148AN XY: 74424
ClinVar
Submissions by phenotype
not provided Uncertain:3
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This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 138 of the COX4I2 protein (p.Glu138Lys). This variant is present in population databases (rs119455950, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with COX4I2-related conditions (PMID: 19268275). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2655). 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 tolerated. Studies have shown that this missense change alters COX4I2 gene expression (PMID: 19268275). 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. -
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Pancreatic insufficiency-anemia-hyperostosis syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at