dbSNP rs113722817: EARS2:p.Arg6Gly (chr16-23557328-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:8

Conservation

PhyloP100: 0.0880

Publications

6 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

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.16A>G	p.Arg6Gly	missense	Exon 1 of 9	NP_001077083.1	Q5JPH6-1
EARS2	NM_001308211.1		c.16A>G	p.Arg6Gly	missense	Exon 1 of 8	NP_001295140.1	Q5JPH6-2
EARS2	NR_003501.2		n.23A>G		non_coding_transcript_exon	Exon 1 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EARS2	ENST00000449606.7	TSL:1 MANE Select	c.16A>G	p.Arg6Gly	missense	Exon 1 of 9	ENSP00000395196.2	Q5JPH6-1
EARS2	ENST00000563232.1	TSL:1	c.16A>G	p.Arg6Gly	missense	Exon 1 of 8	ENSP00000456218.1	Q5JPH6-2
EARS2	ENST00000564501.5	TSL:5	c.16A>G	p.Arg6Gly	missense	Exon 1 of 9	ENSP00000457107.1	H3BTB7

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

GnomAD2 exomes

AF:

0.00627

AC:

965

AN:

154028

AF XY:

0.00619

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 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

African (AFR)

AF:

0.00139

AC:

AN:

32490

American (AMR)

AF:

0.00692

AC:

250

AN:

36112

Ashkenazi Jewish (ASJ)

AF:

0.00645

AC:

162

AN:

25108

East Asian (EAS)

AF:

0.0000269

AC:

AN:

37190

South Asian (SAS)

AF:

0.00576

AC:

463

AN:

80340

European-Finnish (FIN)

AF:

0.00133

AC:

AN:

35288

Middle Eastern (MID)

AF:

0.0114

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

0.00816

AC:

8861

AN:

1086506

Other (OTH)

AF:

0.00628

AC:

367

AN:

58396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

581

1162

1743

2324

2905

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

340

680

1020

1360

1700

<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:

0.00486

AC:

740

AN:

152294

Hom.:

Cov.:

AF XY:

0.00463

AC XY:

345

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41572

American (AMR)

AF:

0.00549

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00577

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00435

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00798

AC:

543

AN:

68012

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

128

170

213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00783

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

EARS2-related disorder (1)

Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.13

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.088

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.3

REVEL

Benign

0.037

Sift

Uncertain

0.023

Sift4G

Benign

0.093

Polyphen

0.0

Vest4

0.30

MVP

0.35

MPC

0.21

ClinPred

0.0063

GERP RS

1.1

PromoterAI

-0.0059

Neutral

(source)

Varity_R

0.10

gMVP

0.47

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over