rs397514592
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001083614.2(EARS2):c.610G>A(p.Gly204Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )
Consequence
EARS2
NM_001083614.2 missense
NM_001083614.2 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 7.42
Genes affected
EARS2 (HGNC:29419): (glutamyl-tRNA synthetase 2, mitochondrial) This gene encodes a member of the class I family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. This protein is encoded by the nuclear genome but is likely to be imported to the mitochondrion where it is thought to catalyze the ligation of glutamate to tRNA molecules. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 12 (COXPD12). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
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MetaRNN computational evidence supports a deleterious effect, 0.854
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EARS2 | NM_001083614.2 | c.610G>A | p.Gly204Ser | missense_variant | 4/9 | ENST00000449606.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EARS2 | ENST00000449606.7 | c.610G>A | p.Gly204Ser | missense_variant | 4/9 | 1 | NM_001083614.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152224Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248906Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135146
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GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461020Hom.: 0 Cov.: 30 AF XY: 0.0000289 AC XY: 21AN XY: 726830
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74376
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2012 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 15, 2022 | Variant summary: EARS2 c.610G>A (p.Gly204Ser) results in a non-conservative amino acid change located in the Glutamyl/glutaminyl-tRNA synthetase, class Ib, catalytic domain (IPR020058) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 248906 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.610G>A has been reported in the literature in at least one compound heterozygous individual affected with Leukoencephalopathy-Thalamus And Brainstem Anomalies-High Lactate Syndrome (Steenweg_2012). This data does not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 29, 2023 | ClinVar contains an entry for this variant (Variation ID: 39790). This missense change has been observed in individual(s) with clinical features of EARS2-related conditions (PMID: 22492562). This variant is present in population databases (rs397514592, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 204 of the EARS2 protein (p.Gly204Ser). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EARS2 protein function. 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
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
H;H;.;H
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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