chr2-88627211-C-CCAGCAG
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS1
The NM_004836.7(EIF2AK3):c.63_64insCTGCTG(p.Leu20_Leu21dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 0)
Exomes 𝑓: 0.00021 ( 0 hom. )
Consequence
EIF2AK3
NM_004836.7 inframe_insertion
NM_004836.7 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.853
Genes affected
EIF2AK3 (HGNC:3255): (eukaryotic translation initiation factor 2 alpha kinase 3) The protein encoded by this gene phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2, leading to its inactivation, and thus to a rapid reduction of translational initiation and repression of global protein synthesis. This protein is thought to modulate mitochondrial function. It is a type I membrane protein located in the endoplasmic reticulum (ER), where it is induced by ER stress caused by malfolded proteins. Mutations in this gene are associated with Wolcott-Rallison syndrome. [provided by RefSeq, Sep 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP6
Variant 2-88627211-C-CCAGCAG is Benign according to our data. Variant chr2-88627211-C-CCAGCAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1061835.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000132 (20/151044) while in subpopulation EAS AF= 0.000393 (2/5088). AF 95% confidence interval is 0.000125. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| EIF2AK3 | NM_004836.7 | c.63_64insCTGCTG | p.Leu20_Leu21dup | inframe_insertion | 1/17 | ENST00000303236.9 | NP_004827.4 | |
| EIF2AK3 | XM_047446430.1 | c.63_64insCTGCTG | p.Leu20_Leu21dup | inframe_insertion | 1/12 | XP_047302386.1 | ||
| EIF2AK3 | XM_047446428.1 | c.17+477_17+478insCTGCTG | intron_variant | XP_047302384.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| EIF2AK3 | ENST00000303236.9 | c.63_64insCTGCTG | p.Leu20_Leu21dup | inframe_insertion | 1/17 | 1 | NM_004836.7 | ENSP00000307235 | P1 | |
| EIF2AK3 | ENST00000682892.1 | c.-145-13359_-145-13358insCTGCTG | intron_variant | ENSP00000507214 | ||||||
| EIF2AK3 | ENST00000652099.1 | c.61_62insCTGCTG | p.Leu20_Leu21dup | inframe_insertion, NMD_transcript_variant | 1/18 | ENSP00000498211 | ||||
| EIF2AK3 | ENST00000652423.1 | c.63_64insCTGCTG | p.Leu20_Leu21dup | inframe_insertion, NMD_transcript_variant | 1/4 | ENSP00000498948 |
Frequencies
GnomAD3 genomes 0.000132 AC: 20AN: 151044Hom.: 0 Cov.: 0
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GnomAD3 exomes AF: 0.000199 AC: 13AN: 65220Hom.: 0 AF XY: 0.000241 AC XY: 9AN XY: 37308
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GnomAD4 exome AF: 0.000206 AC: 263AN: 1278938Hom.: 0 Cov.: 0 AF XY: 0.000200 AC XY: 126AN XY: 630080
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GnomAD4 genome 0.000132 AC: 20AN: 151044Hom.: 0 Cov.: 0 AF XY: 0.000122 AC XY: 9AN XY: 73738
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 01, 2022 | This variant, c.58_63dup, results in the insertion of 2 amino acid(s) of the EIF2AK3 protein (p.Leu20_Leu21dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with EIF2AK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1061835). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Connective tissue disorder Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 19, 2020 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at