rs763717023

Variant names:

• chr13-110642433-A-G
• rs763717023
• NM_024537.4:c.1505T>C
• CARS2 p.Leu502Pro

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.25
• Publications: 0 publications found

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), G2P, Laboratory for Molecular Medicine, Orphanet
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS2	NM_024537.4	MANE Select	c.1505T>C	p.Leu502Pro	missense	Exon 14 of 15	NP_078813.1	Q9HA77
	CARS2	NM_001352252.2		c.719T>C	p.Leu240Pro	missense	Exon 15 of 16	NP_001339181.1
	CARS2	NR_147941.1		n.1589T>C		non_coding_transcript_exon	Exon 16 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS2	ENST00000257347.9	TSL:1 MANE Select	c.1505T>C	p.Leu502Pro	missense	Exon 14 of 15	ENSP00000257347.4	Q9HA77
	CARS2	ENST00000939453.1		c.1649T>C	p.Leu550Pro	missense	Exon 14 of 15	ENSP00000609512.1
	CARS2	ENST00000890914.1		c.1499T>C	p.Leu500Pro	missense	Exon 14 of 15	ENSP00000560973.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000593 AC: 14 AN: 236114 AF XY: 0.0000467

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: 14 AN: 1453870 Hom.: 0 Cov.: 33 AF XY: 0.00000830 AC XY: 6 AN XY: 722700

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.000295 AC: 13 AN: 44044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25886

East Asian (EAS) AF: 0.00 AC: 0 AN: 39310

South Asian (SAS) AF: 0.00 AC: 0 AN: 84922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108884

Other (OTH) AF: 0.00 AC: 0 AN: 60032

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Combined oxidative phosphorylation defect type 27 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Varity_R		0.93
gMVP		0.87
Mutation Taster		=17/83	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs763717023;

hg19: chr13-111294780;