rs187662524

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001083614.2(EARS2):c.1045G>A(p.Glu349Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0015 in 1,613,952 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E349V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 2 hom. )

Consequence

EARS2
NM_001083614.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: 4.65

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

EARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020168513).

BP6

Variant 16-23532679-C-T is Benign according to our data. Variant chr16-23532679-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 425101.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00143 (217/152270) while in subpopulation AMR AF = 0.00307 (47/15290). AF 95% confidence interval is 0.00237. There are 2 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EARS2	NM_001083614.2 link	c.1045G>A	p.Glu349Lys	missense_variant	Exon 5 of 9	ENST00000449606.7	NP_001077083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EARS2	ENST00000449606.7 link	c.1045G>A	p.Glu349Lys	missense_variant	Exon 5 of 9	1	NM_001083614.2	ENSP00000395196.2

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

217

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00203

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00138

AC:

344

AN:

249160

AF XY:

0.00134

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00237

Gnomad OTH exome

AF:

0.000991

GnomAD4 exome

AF:

0.00150

AC:

2199

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

1087

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.00132

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00218

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00176

AC:

1952

AN:

1111902

Other (OTH)

AF:

0.00152

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

100

201

301

402

502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00143

AC:

217

AN:

152270

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41556

American (AMR)

AF:

0.00307

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00203

AC:

138

AN:

68012

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00219

Hom.:

Bravo

AF:

0.00151

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00266

AC:

ExAC

AF:

0.00130

AC:

157

EpiCase

AF:

0.00311

EpiControl

AF:

0.00373

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 12, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28748215, 28748214) -

Aug 01, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EARS2: BS2 -

Mar 09, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Uncertain:2

Feb 22, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases

Benign:1

May 13, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Mitochondrial disease

Benign:1

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;D;D;.

Eigen

Benign

-0.029

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;.;D;D

M_CAP

Benign

0.0081

MetaRNN

Benign

0.020

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.62

N;N;.;N

PhyloP100

4.7

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.5

D;D;D;D

REVEL

Benign

0.089

Sift

Uncertain

0.014

D;D;T;T

Sift4G

Benign

0.097

T;T;T;T

Polyphen

0.016

B;B;.;.

Vest4

0.49

MVP

0.63

MPC

0.22

ClinPred

0.043

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.25

gMVP

0.37

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over