chr20-63495062-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1_ModeratePM2PP2PP3_StrongPP5_Very_Strong
The NM_001958.5(EEF1A2):c.364G>A(p.Glu122Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.
Frequency
Genomes: not found (cov: 34)
Consequence
EEF1A2
NM_001958.5 missense
NM_001958.5 missense
Scores
6
11
2
Clinical Significance
Conservation
PhyloP100: 7.80
Genes affected
EEF1A2 (HGNC:3192): (eukaryotic translation elongation factor 1 alpha 2) This gene encodes an isoform of the alpha subunit of the elongation factor-1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome. This isoform (alpha 2) is expressed in brain, heart and skeletal muscle, and the other isoform (alpha 1) is expressed in brain, placenta, lung, liver, kidney, and pancreas. This gene may be critical in the development of ovarian cancer. [provided by RefSeq, Mar 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PS1
Transcript NM_001958.5 (EEF1A2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EEF1A2. . Gene score misZ: 4.8166 (greater than the threshold 3.09). Trascript score misZ: 6.0564 (greater than threshold 3.09). The gene has 34 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. GenCC has associacion of the gene with autosomal dominant non-syndromic intellectual disability, undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 33.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.957
PP5
Variant 20-63495062-C-T is Pathogenic according to our data. Variant chr20-63495062-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 192252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
34
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratoire de Génétique Moléculaire, CHU Bordeaux | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 13, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32196822, 31477274, 27441201, 23033978, 23647072, 26740508, 19636410, 28911200, 28378778, 24697219, 3066688, 26682508) - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Genetics, Robert DEBRE University Hospital | Apr 26, 2018 | - - |
Developmental and epileptic encephalopathy, 33 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Oct 25, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Mar 08, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 122 of the EEF1A2 protein (p.Glu122Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurological disease, including epilepsy and intellectual disability (PMID: 24697219, 26682508, 27441201). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 192252). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EEF1A2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects EEF1A2 function (PMID: 3066688). For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 18, 2015 | - - |
Intellectual disability, autosomal dominant 38 Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 04, 2018 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing [PMID 24697219, 26682508, 27441201] - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2017 | - - |
EEF1A2-related developmental and degenerative epileptic-dyskinetic encephalopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Epilepsy Neurogenetics Initiative, Children's Hospital of Philadelphia | Feb 13, 2020 | The EEF1A2 c.364G>A; p.Glu122Lys variant has been identified in three individuals with a developmental and epileptic encephalopathy characterized by global developmental delays, moderate to severe intellectual disability, and intractable infantile or early childhood onset epilepsy. One individual had a hyperkinetic movement disorder characterized by choreoathetosis. The variant is confirmed de novo in two individuals; testing of both parents was not performed in the third individual. The variant is absent from population databases (ExAC, gnomAD) and is predicted to have a damaging effect on the protein by in silico models. Therefore, this variant has been classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;.
Sift4G
Uncertain
D;.;.
Polyphen
D;.;.
Vest4
MutPred
Gain of methylation at E122 (P = 0.0026);Gain of methylation at E122 (P = 0.0026);Gain of methylation at E122 (P = 0.0026);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at