Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_024537.4(CARS2):c.666C>A(p.Asp222Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CARS2
NM_024537.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.952

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31387138).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024537.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CARS2	NM_024537.4	MANE Select	c.666C>A	p.Asp222Glu	missense	Exon 7 of 15	NP_078813.1
CARS2	NM_001352253.3		c.666C>A	p.Asp222Glu	missense	Exon 7 of 9	NP_001339182.1
CARS2	NR_147941.1		n.637C>A		non_coding_transcript_exon	Exon 8 of 17

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CARS2	ENST00000257347.9	TSL:1 MANE Select	c.666C>A	p.Asp222Glu	missense	Exon 7 of 15	ENSP00000257347.4
CARS2	ENST00000465145.5	TSL:5	n.591C>A		non_coding_transcript_exon	Exon 8 of 9
CARS2	ENST00000481787.6	TSL:5	n.100C>A		non_coding_transcript_exon	Exon 2 of 10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454774

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722756

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33348

American (AMR)

AF:

0.0000225

AC:

AN:

44408

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25966

East Asian (EAS)

AF:

0.00

AC:

AN:

39260

South Asian (SAS)

AF:

0.00

AC:

AN:

85836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107026

Other (OTH)

AF:

0.00

AC:

AN:

59996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Combined oxidative phosphorylation defect type 27 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.14

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.71

M_CAP

Benign

0.010

MetaRNN

Benign

0.31

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.42

PhyloP100

0.95

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.8

REVEL

Benign

0.061

Sift

Benign

0.23

Sift4G

Benign

0.67

Polyphen

0.0080

Vest4

0.48

MutPred

0.42

Gain of ubiquitination at K223 (P = 0.1106)

MVP

0.36

MPC

0.17

ClinPred

0.67

GERP RS

4.4

PromoterAI

0.0012

Neutral

(source)

Varity_R

0.089

gMVP

0.38

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

13-110677093-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over