13-110705993-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024537.4(CARS2):c.101C>A(p.Ala34Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000742 in 1,348,434 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. 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. A34G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

CARS2
NM_024537.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.811

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15800402).

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.101C>A	p.Ala34Glu	missense	Exon 1 of 15	NP_078813.1
CARS2	NM_001352253.3		c.101C>A	p.Ala34Glu	missense	Exon 1 of 9	NP_001339182.1
CARS2	NR_147942.2		n.124C>A		non_coding_transcript_exon	Exon 1 of 17

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CARS2	ENST00000257347.9	TSL:1 MANE Select	c.101C>A	p.Ala34Glu	missense	Exon 1 of 15	ENSP00000257347.4
CARS2	ENST00000537394.5	TSL:5	n.101C>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000437962.1
CARS2	ENST00000539269.5	TSL:3	n.59C>A		non_coding_transcript_exon	Exon 1 of 8	ENSP00000440420.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.42e-7

AC:

AN:

1348434

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

665442

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27810

American (AMR)

AF:

0.00

AC:

AN:

31136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23234

East Asian (EAS)

AF:

0.00

AC:

AN:

32194

South Asian (SAS)

AF:

0.00

AC:

AN:

74774

European-Finnish (FIN)

AF:

0.0000274

AC:

AN:

36496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5382

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1061478

Other (OTH)

AF:

0.00

AC:

AN:

55930

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.16

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.096

LIST_S2

Benign

0.66

M_CAP

Benign

0.015

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

PhyloP100

0.81

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.0

REVEL

Benign

0.14

Sift

Benign

0.14

Sift4G

Uncertain

0.028

Polyphen

0.93

Vest4

0.17

MutPred

0.40

Loss of methylation at R32 (P = 0.0682)

MVP

0.33

MPC

3.2

ClinPred

0.41

GERP RS

-1.4

PromoterAI

-0.052

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.096

gMVP

0.45

Mutation Taster

=89/11

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over