rs113722817

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001083614.2(EARS2):c.16A>G(p.Arg6Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0071 in 1,549,354 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0073 ( 57 hom. )

Consequence

EARS2
NM_001083614.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0880

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004332006).

BP6

Variant 16-23557328-T-C is Benign according to our data. Variant chr16-23557328-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 137190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00486 (740/152294) while in subpopulation NFE AF= 0.00798 (543/68012). AF 95% confidence interval is 0.00743. There are 4 homozygotes in gnomad4. There are 345 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EARS2	NM_001083614.2 linkuse as main transcript	c.16A>G	p.Arg6Gly	missense_variant	1/9	ENST00000449606.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EARS2	ENST00000449606.7 linkuse as main transcript	c.16A>G	p.Arg6Gly	missense_variant	1/9	1	NM_001083614.2	P1	Q5JPH6-1

Frequencies

GnomAD3 genomes

AF:

0.00488

AC:

742

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00549

Gnomad ASJ

AF:

0.00577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00798

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00627

AC:

965

AN:

154028

Hom.:

AF XY:

0.00619

AC XY:

521

AN XY:

84204

show subpopulations

Gnomad AFR exome

AF:

0.00115

Gnomad AMR exome

AF:

0.00678

Gnomad ASJ exome

AF:

0.00663

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00609

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00840

Gnomad OTH exome

AF:

0.00801

GnomAD4 exome

AF:

0.00734

AC:

10260

AN:

1397060

Hom.:

Cov.:

AF XY:

0.00737

AC XY:

5090

AN XY:

691004

show subpopulations

Gnomad4 AFR exome

AF:

0.00139

Gnomad4 AMR exome

AF:

0.00692

Gnomad4 ASJ exome

AF:

0.00645

Gnomad4 EAS exome

AF:

0.0000269

Gnomad4 SAS exome

AF:

0.00576

Gnomad4 FIN exome

AF:

0.00133

Gnomad4 NFE exome

AF:

0.00816

Gnomad4 OTH exome

AF:

0.00628

GnomAD4 genome

AF:

0.00486

AC:

740

AN:

152294

Hom.:

Cov.:

AF XY:

0.00463

AC XY:

345

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00549

Gnomad4 ASJ

AF:

0.00577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00798

Gnomad4 OTH

AF:

0.00804

Alfa

AF:

0.00820

Hom.:

Bravo

AF:

0.00533

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.000798

AC:

ESP6500EA

AF:

0.00569

AC:

ExAC

AF:

0.00467

AC:

531

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	EARS2: BP4, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

EARS2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 05, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

Cadd

Benign

Dann

Benign

0.88

DEOGEN2

Benign

0.13

T;T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.71

T;.;T;T

MetaRNN

Benign

0.0043

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;.;N

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.037

Sift

Uncertain

0.023

D;D;D;D

Sift4G

Benign

0.093

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.30

MVP

0.35

MPC

0.21

ClinPred

0.0063

GERP RS

1.1

Varity_R

0.10

gMVP

0.47

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over