rs142034206

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_024537.4(CARS2):c.563C>T(p.Thr188Met) variant causes a missense 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T188A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00077 ( 0 hom. )

Consequence

CARS2
NM_024537.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:6

Conservation

PhyloP100: 7.48

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000292 (44/150892) while in subpopulation NFE AF= 0.000531 (36/67812). AF 95% confidence interval is 0.000393. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARS2	NM_024537.4 linkuse as main transcript	c.563C>T	p.Thr188Met	missense_variant	5/15	ENST00000257347.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARS2	ENST00000257347.9 linkuse as main transcript	c.563C>T	p.Thr188Met	missense_variant	5/15	1	NM_024537.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000292

AC:

AN:

150892

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000294

AC:

AN:

241100

Hom.:

AF XY:

0.000360

AC XY:

AN XY:

130552

show subpopulations

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 SAS exome

AF:

0.0000353

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.:

Cov.:

AF XY:

0.000745

AC XY:

530

AN XY:

711436

show subpopulations

Gnomad4 AFR exome

AF:

0.0000936

Gnomad4 AMR exome

AF:

0.000120

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000359

Gnomad4 FIN exome

AF:

0.000151

Gnomad4 NFE exome

AF:

0.000965

Gnomad4 OTH exome

AF:

0.000457

GnomAD4 genome

AF:

0.000292

AC:

AN:

150892

Hom.:

Cov.:

AF XY:

0.000245

AC XY:

AN XY:

73564

show subpopulations

Gnomad4 AFR

AF:

0.000122

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000531

Gnomad4 OTH

AF:

0.000482

Alfa

AF:

0.000544

Hom.:

Bravo

AF:

0.000306

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.000383

EpiControl

AF:

0.000656

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 27

Pathogenic:1Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 27, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2022	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 188 of the CARS2 protein (p.Thr188Met). This variant is present in population databases (rs142034206, gnomAD 0.05%). This missense change has been observed in individual(s) with epilepsy and intellectual disability (PMID: 30139652). ClinVar contains an entry for this variant (Variation ID: 475631). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 17, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 13, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 16, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 30, 2023

Variant summary: CARS2 c.563C>T (p.Thr188Met) results in a non-conservative amino acid change located in the tRNA synthetases class I, catalytic domain (IPR032678) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 241100 control chromosomes (gnomAD). c.563C>T has been reported in the literature in individuals affected with Alpers-Huttenlocher syndrome (Samanta_2018, Almubarak_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36360262, 34690748, 34426522, 30139652). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.28

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.

Eigen

Uncertain

0.37

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

D;T

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.50

D;D

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-4.4

D;D

REVEL

Benign

0.28

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;.

Vest4

0.71

MVP

0.59

MPC

0.70

ClinPred

0.75

GERP RS

3.6

Varity_R

0.16

gMVP

0.81

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over