rs763717023

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_024537.4(CARS2):c.1505T>C(p.Leu502Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000963 in 1,453,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L502M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CARS2
NM_024537.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.25

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARS2	NM_024537.4 link	c.1505T>C	p.Leu502Pro	missense_variant	Exon 14 of 15	ENST00000257347.9	NP_078813.1	Q9HA77B7Z7E6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARS2	ENST00000257347.9 link	c.1505T>C	p.Leu502Pro	missense_variant	Exon 14 of 15	1	NM_024537.4	ENSP00000257347.4		Q9HA77

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000593

AC:

AN:

236114

AF XY:

0.0000467

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000387

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000948

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000963

AC:

AN:

1453870

Hom.:

Cov.:

AF XY:

0.00000830

AC XY:

AN XY:

722700

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33354

American (AMR)

AF:

0.000295

AC:

AN:

44044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25886

East Asian (EAS)

AF:

0.00

AC:

AN:

39310

South Asian (SAS)

AF:

0.00

AC:

AN:

84922

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108884

Other (OTH)

AF:

0.00

AC:

AN:

60032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 27

Uncertain:2

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 502 of the CARS2 protein (p.Leu502Pro). This variant is present in population databases (rs763717023, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 569707). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 12, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.03% (13/33610) (https://gnomad.broadinstitute.org/variant/13-111294780-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:569707). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.81

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.7

PhyloP100

4.2

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.9

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.85

MutPred

0.57

Gain of disorder (P = 0.0099);

MVP

0.70

MPC

0.89

ClinPred

0.90

GERP RS

5.1

Varity_R

0.93

gMVP

0.87

Mutation Taster

=17/83

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over