chr13-110642403-C-T

Position:

chr13-110642403-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_024537.4(CARS2):c.1535G>A(p.Arg512Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,582,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CARS2
NM_024537.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.732

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0057305694).

BP6

Variant 13-110642403-C-T is Benign according to our data. Variant chr13-110642403-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542311.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARS2	NM_024537.4 link	c.1535G>A	p.Arg512Gln	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 link	c.1535G>A	p.Arg512Gln	missense_variant	14/15	1	NM_024537.4	ENSP00000257347.4		Q9HA77

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000435

AC:

AN:

200120

Hom.:

AF XY:

0.000296

AC XY:

AN XY:

107946

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000998

Gnomad ASJ exome

AF:

0.000221

Gnomad EAS exome

AF:

0.00220

Gnomad SAS exome

AF:

0.000116

Gnomad FIN exome

AF:

0.000331

Gnomad NFE exome

AF:

0.000153

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000155

AC:

222

AN:

1429974

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

101

AN XY:

708648

show subpopulations

Gnomad4 AFR exome

AF:

0.0000915

Gnomad4 AMR exome

AF:

0.000982

Gnomad4 ASJ exome

AF:

0.000196

Gnomad4 EAS exome

AF:

0.00169

Gnomad4 SAS exome

AF:

0.0000973

Gnomad4 FIN exome

AF:

0.000220

Gnomad4 NFE exome

AF:

0.0000721

Gnomad4 OTH exome

AF:

0.000135

GnomAD4 genome

AF:

0.000217

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000287

Hom.:

Bravo

AF:

0.000321

ExAC

AF:

0.000299

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2024

Reported in an individual with schizophrenia; however, additional clinical information was not provided (PMID: 26740555); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28719003, 26740555) -

Combined oxidative phosphorylation defect type 27

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2025

- -

CARS2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2022

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.72

CADD

Benign

9.3

DANN

Benign

0.93

DEOGEN2

Benign

0.15

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.67

M_CAP

Benign

0.0030

MetaRNN

Benign

0.0057

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.54

REVEL

Benign

0.027

Sift

Benign

0.26

Sift4G

Benign

0.25

Polyphen

0.041

Vest4

0.29

MVP

0.27

MPC

0.20

ClinPred

0.024

GERP RS

0.45

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.014

gMVP

0.42

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