rs376103091

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PP5_Very_Strong

The NM_001083614.2(EARS2):c.322C>T(p.Arg108Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,606,474 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R108R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

EARS2
NM_001083614.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 3.54

Publications

12 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
mitochondrial disease
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: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001083614.2

PP5

Variant 16-23544677-G-A is Pathogenic according to our data. Variant chr16-23544677-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083614.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EARS2	NM_001083614.2	MANE Select	c.322C>T	p.Arg108Trp	missense	Exon 3 of 9	NP_001077083.1	Q5JPH6-1
EARS2	NM_001308211.1		c.322C>T	p.Arg108Trp	missense	Exon 3 of 8	NP_001295140.1	Q5JPH6-2
EARS2	NR_003501.2		n.329C>T		non_coding_transcript_exon	Exon 3 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EARS2	ENST00000449606.7	TSL:1 MANE Select	c.322C>T	p.Arg108Trp	missense	Exon 3 of 9	ENSP00000395196.2	Q5JPH6-1
EARS2	ENST00000563232.1	TSL:1	c.322C>T	p.Arg108Trp	missense	Exon 3 of 8	ENSP00000456218.1	Q5JPH6-2
EARS2	ENST00000564987.1	TSL:1	n.60-114C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000151

AC:

AN:

231208

AF XY:

0.000167

show subpopulations

Gnomad AFR exome

AF:

0.0000729

Gnomad AMR exome

AF:

0.0000612

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000269

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000142

AC:

207

AN:

1454244

Hom.:

Cov.:

AF XY:

0.000152

AC XY:

110

AN XY:

722864

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33386

American (AMR)

AF:

0.0000690

AC:

AN:

43474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25900

East Asian (EAS)

AF:

0.00

AC:

AN:

39508

South Asian (SAS)

AF:

0.000106

AC:

AN:

85136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4734

European-Non Finnish (NFE)

AF:

0.000166

AC:

184

AN:

1109528

Other (OTH)

AF:

0.000117

AC:

AN:

60074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000184

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.000203

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000486

AC:

ExAC

AF:

0.000149

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (6)

not provided (4)

Inborn genetic diseases (1)

See cases (1)

Seizure;C0235081:Limb tremor;C0240635:High palate;C0424503:Abnormal facial shape;C0494475:Bilateral tonic-clonic seizure;C0557874:Global developmental delay;C0857379:Abnormal pinna morphology;C1837260:Prominent forehead;C1854301:Motor delay (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.5

PhyloP100

3.5

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.19

Sift

Benign

0.11

Sift4G

Benign

0.18

Polyphen

0.99

Vest4

0.55

MVP

0.61

MPC

0.63

ClinPred

0.24

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.73

Mutation Taster

=8/92

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over