rs142034206

Variant names:

• chr13-110687729-G-A
• rs142034206
• NM_024537.4:c.563C>T

Variant summary

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

The NM_001352252.2(CARS2):​c.-437C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000723 in 1,578,396 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (0 hom.)
• Consequence: CARS2 NM_001352252.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:7
• Conservation: PhyloP100: 7.48
• Publications: 9 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), Orphanet, G2P, Laboratory for Molecular Medicine
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352252.2. 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.563C>T	p.Thr188Met	missense	Exon 5 of 15	NP_078813.1	Q9HA77
	CARS2	NM_001352252.2		c.-437C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 16	NP_001339181.1
	CARS2	NM_001352253.3		c.563C>T	p.Thr188Met	missense	Exon 5 of 9	NP_001339182.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS2	ENST00000257347.9	TSL:1 MANE Select	c.563C>T	p.Thr188Met	missense	Exon 5 of 15	ENSP00000257347.4	Q9HA77
	CARS2	ENST00000939453.1		c.563C>T	p.Thr188Met	missense	Exon 5 of 15	ENSP00000609512.1
	CARS2	ENST00000890914.1		c.557C>T	p.Thr186Met	missense	Exon 5 of 15	ENSP00000560973.1

Frequencies

GnomAD3 genomes AF: 0.000292 AC: 44 AN: 150892 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000531

Gnomad OTH AF: 0.000482

GnomAD2 exomes AF: 0.000294 AC: 71 AN: 241100 AF XY: 0.000360

Gnomad AFR exome AF: 0.0000627

Gnomad AMR exome AF: 0.000126

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.000561

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.000768 AC: 1097 AN: 1427504 Hom.: 0 Cov.: 29 AF XY: 0.000745 AC XY: 530 AN XY: 711436

African (AFR) AF: 0.0000936 AC: 3 AN: 32052

American (AMR) AF: 0.000120 AC: 5 AN: 41746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25526

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39380

South Asian (SAS) AF: 0.0000359 AC: 3 AN: 83484

European-Finnish (FIN) AF: 0.000151 AC: 8 AN: 53120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5280

European-Non Finnish (NFE) AF: 0.000965 AC: 1050 AN: 1087872

Other (OTH) AF: 0.000457 AC: 27 AN: 59044

GnomAD4 genome AF: 0.000292 AC: 44 AN: 150892 Hom.: 0 Cov.: 32 AF XY: 0.000245 AC XY: 18 AN XY: 73564

African (AFR) AF: 0.000122 AC: 5 AN: 41014

American (AMR) AF: 0.000132 AC: 2 AN: 15146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000531 AC: 36 AN: 67812

Other (OTH) AF: 0.000482 AC: 1 AN: 2076

Alfa AF: 0.000525 Hom.: 0

Bravo AF: 0.000306

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000383

EpiControl AF: 0.000656

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	4	-	Combined oxidative phosphorylation defect type 27 (5)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.4	D
REVEL	Benign	0.28
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.71
MVP		0.59
MPC		0.70
ClinPred		0.75	D
GERP RS		3.6
Varity_R		0.16
gMVP		0.81
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs142034206; hg19: chr13-111340076; COSMIC: COSV57283840; COSMIC: COSV57283840;