rs746838793

Positions:

• chr16-23534897-C-A
• chr16-23534897-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001083614.2(EARS2):​c.949G>T​(p.Gly317Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,422,392 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: EARS2 NM_001083614.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.53

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]

EARS2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804
• PP5: Variant 16-23534897-C-A is Pathogenic according to our data. Variant chr16-23534897-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 318550.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EARS2	NM_001083614.2	c.949G>T	p.Gly317Cys	missense_variant	4/9	ENST00000449606.7	NP_001077083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EARS2	ENST00000449606.7	c.949G>T	p.Gly317Cys	missense_variant	4/9	1	NM_001083614.2	ENSP00000395196.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.000126 AC: 28 AN: 222164 Hom.: 0 AF XY: 0.0000844 AC XY: 10 AN XY: 118524

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000798

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000371

GnomAD4 exome AF: 0.0000232 AC: 33 AN: 1422392 Hom.: 0 Cov.: 30 AF XY: 0.0000200 AC XY: 14 AN XY: 701616

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.000633

Gnomad4 ASJ exome AF: 0.0000860

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.18e-7

Gnomad4 OTH exome AF: 0.0000341

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000227

ExAC AF: 0.0000992 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2023

For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt EARS2 protein function. ClinVar contains an entry for this variant (Variation ID: 318550). This missense change has been observed in individual(s) with combined oxidative phosphorylation deficiency (PMID: 22492562, 28973083, 33855712). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs746838793, gnomAD 0.06%). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 317 of the EARS2 protein (p.Gly317Cys). -

Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The EARS2 c.949G>T (p.Gly317Cys) missense variant has been reported in one study in which it was found in a compound heterozygous state with a second missense variant in one patient who presented with a mild form of combined oxidative phosphorylation deficiency based on disease course and MRI findings (Steenweg et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.00115 in the Latino population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Gly317Cys variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for combined oxidative phosphorylation deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.5	H;H;.;H
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-9.0	D;D;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.94
MutPred		0.66		Loss of disorder (P = 0.0332);Loss of disorder (P = 0.0332);Loss of disorder (P = 0.0332);Loss of disorder (P = 0.0332);
MVP		0.76
MPC		0.72
ClinPred		0.96	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs746838793; hg19: chr16-23546218;