dbSNP rs140082252: CARS2:p.Asp196Tyr (chr13-110683120-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_024537.4(CARS2):c.586G>T(p.Asp196Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D196N) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CARS2
NM_024537.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.67

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARS2	NM_024537.4 link	c.586G>T	p.Asp196Tyr	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.586G>T	p.Asp196Tyr	missense_variant	Exon 6 of 15	1	NM_024537.4	ENSP00000257347.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442940

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717394

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32232

American (AMR)

AF:

0.00

AC:

AN:

41214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25732

East Asian (EAS)

AF:

0.00

AC:

AN:

38350

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4802

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104418

Other (OTH)

AF:

0.00

AC:

AN:

59480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.014

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

-0.089

MutationAssessor

Pathogenic

3.0

PhyloP100

2.7

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-7.2

REVEL

Uncertain

0.47

Sift

Benign

0.042

Sift4G

Uncertain

0.040

Vest4

0.77

ClinPred

0.99

GERP RS

5.2

Varity_R

0.89

gMVP

0.93

Mutation Taster

=45/55

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over