rs878853014

Positions:

• chr16-23535037-T-C
• chr16-23535037-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001083614.2(EARS2):​c.809A>G​(p.His270Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EARS2 NM_001083614.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0440

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08806473).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EARS2	NM_001083614.2	c.809A>G	p.His270Arg	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.809A>G	p.His270Arg	missense_variant	4/9	1	NM_001083614.2	ENSP00000395196.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Apr 29, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.016
DANN	Benign	0.65
DEOGEN2	Benign	0.20	T;T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.76	T;.;T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.088	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.99	N;N;.;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.56	N;N;N;N
REVEL	Benign	0.072
Sift	Benign	0.73	T;T;T;T
Sift4G	Benign	0.63	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.051
MutPred		0.46		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);
MVP		0.14
MPC		0.20
ClinPred		0.031	T
GERP RS		-8.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs878853014; hg19: chr16-23546358;