rs146355429

Positions:

chr13-110642449-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024537.4(CARS2):c.1489G>A(p.Val497Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000674 in 1,608,110 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00038 ( 6 hom. )

Consequence

CARS2
NM_024537.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.04

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:

CARS2 (HGNC:):

CARS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0106699765).

BP6

Variant 13-110642449-C-T is Benign according to our data. Variant chr13-110642449-C-T is described in ClinVar as [Benign]. Clinvar id is 475619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110642449-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00349 (532/152366) while in subpopulation AFR AF= 0.0119 (497/41592). AF 95% confidence interval is 0.0111. There are 3 homozygotes in gnomad4. There are 258 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARS2	NM_024537.4 linkuse as main transcript	c.1489G>A	p.Val497Ile	missense_variant	14/15	ENST00000257347.9	NP_078813.1	Q9HA77B7Z7E6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARS2	ENST00000257347.9 linkuse as main transcript	c.1489G>A	p.Val497Ile	missense_variant	14/15	1	NM_024537.4	ENSP00000257347.4		Q9HA77

Frequencies

GnomAD3 genomes

AF:

0.00349

AC:

531

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

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:

0.00

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000788

AC:

188

AN:

238530

Hom.:

AF XY:

0.000524

AC XY:

AN XY:

129670

show subpopulations

Gnomad AFR exome

AF:

0.0115

Gnomad AMR exome

AF:

0.000444

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000341

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000187

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.000379

AC:

552

AN:

1455744

Hom.:

Cov.:

AF XY:

0.000307

AC XY:

222

AN XY:

723768

show subpopulations

Gnomad4 AFR exome

AF:

0.0134

Gnomad4 AMR exome

AF:

0.000565

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000587

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000631

Gnomad4 OTH exome

AF:

0.00115

GnomAD4 genome

AF:

0.00349

AC:

532

AN:

152366

Hom.:

Cov.:

AF XY:

0.00346

AC XY:

258

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.0119

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.000561

Hom.:

Bravo

AF:

0.00400

ESP6500AA

AF:

0.0130

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00102

AC:

124

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 27

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

CARS2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 29, 2020

This variant is associated with the following publications: (PMID: 21796119) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.7

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.76

REVEL

Benign

0.10

Sift

Benign

0.16

Sift4G

Benign

0.28

Polyphen

0.79

Vest4

0.52

MVP

0.45

MPC

0.46

ClinPred

0.041

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.44

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

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