NM_024537.4:c.647G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024537.4(CARS2):c.647G>A(p.Gly216Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,600,186 control chromosomes in the GnomAD database, including 373 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G216R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 30 hom., cov: 33)

Exomes 𝑓: 0.018 ( 343 hom. )

Consequence

CARS2
NM_024537.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.03

Publications

8 publications found

Variant links:

Genes affected

CARS2 (HGNC:25695): (cysteinyl-tRNA synthetase 2, mitochondrial) This gene encodes a putative 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 cysteine to tRNA molecules. A splice-site mutation in this gene has been associated with a novel progressive myoclonic epilepsy disease with similar symptoms to MERRF syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2017]

CARS2 Gene-Disease associations (from GenCC):

combined oxidative phosphorylation defect type 27
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine, G2P
mitochondrial disease
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

CARS2 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=0.00331226).

BP6

Variant 13-110683059-C-T is Benign according to our data. Variant chr13-110683059-C-T is described in ClinVar as Benign. ClinVar VariationId is 380445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0159 (2424/152302) while in subpopulation AMR AF = 0.0309 (472/15294). AF 95% confidence interval is 0.0286. There are 30 homozygotes in GnomAd4. There are 1261 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARS2	NM_024537.4 link	c.647G>A	p.Gly216Glu	missense_variant	Exon 6 of 15	ENST00000257347.9	NP_078813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARS2	ENST00000257347.9 link	c.647G>A	p.Gly216Glu	missense_variant	Exon 6 of 15	1	NM_024537.4	ENSP00000257347.4

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2425

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00369

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.0308

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0151

Gnomad FIN

AF:

0.0339

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0192

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0196

AC:

4692

AN:

239186

AF XY:

0.0194

show subpopulations

Gnomad AFR exome

AF:

0.00293

Gnomad AMR exome

AF:

0.0368

Gnomad ASJ exome

AF:

0.00193

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0363

Gnomad NFE exome

AF:

0.0189

Gnomad OTH exome

AF:

0.0166

GnomAD4 exome

AF:

0.0185

AC:

26762

AN:

1447884

Hom.:

343

Cov.:

AF XY:

0.0184

AC XY:

13221

AN XY:

720240

show subpopulations

African (AFR)

AF:

0.00274

AC:

AN:

32468

American (AMR)

AF:

0.0363

AC:

1537

AN:

42344

Ashkenazi Jewish (ASJ)

AF:

0.00162

AC:

AN:

25898

East Asian (EAS)

AF:

0.0000260

AC:

AN:

38466

South Asian (SAS)

AF:

0.0189

AC:

1593

AN:

84254

European-Finnish (FIN)

AF:

0.0341

AC:

1811

AN:

53036

Middle Eastern (MID)

AF:

0.00609

AC:

AN:

4436

European-Non Finnish (NFE)

AF:

0.0187

AC:

20679

AN:

1107260

Other (OTH)

AF:

0.0165

AC:

983

AN:

59722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1140

2280

3420

4560

5700

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

772

1544

2316

3088

3860

<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:

0.0159

AC:

2424

AN:

152302

Hom.:

Cov.:

AF XY:

0.0169

AC XY:

1261

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00368

AC:

153

AN:

41572

American (AMR)

AF:

0.0309

AC:

472

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.0151

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0339

AC:

360

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0192

AC:

1305

AN:

68020

Other (OTH)

AF:

0.0156

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

128

256

385

513

641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0170

Hom.:

Bravo

AF:

0.0154

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0195

AC:

168

ExAC

AF:

0.0185

AC:

2250

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 14, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Combined oxidative phosphorylation defect type 27

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.76

CADD

Benign

2.0

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.16

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0033

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.1

PhyloP100

-1.0

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.4

REVEL

Benign

0.060

Sift

Benign

0.40

Sift4G

Benign

0.59

Polyphen

0.0050

Vest4

0.046

MPC

0.24

ClinPred

0.00098

GERP RS

-4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.035

gMVP

0.63

Mutation Taster

=100/0

polymorphism (auto)

(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