rs147216443

Positions:

• chr13-110642407-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024537.4(CARS2):​c.1531G>A​(p.Ala511Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,585,428 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (6 hom.)
• Consequence: CARS2 NM_024537.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.154

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038008988).
• BP6: Variant 13-110642407-C-T is Benign according to our data. Variant chr13-110642407-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 386020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00157 (239/152360) while in subpopulation NFE AF= 0.00154 (105/68026). AF 95% confidence interval is 0.0013. There are 1 homozygotes in gnomad4. There are 155 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARS2	NM_024537.4	c.1531G>A	p.Ala511Thr	missense_variant	14/15	ENST00000257347.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARS2	ENST00000257347.9	c.1531G>A	p.Ala511Thr	missense_variant	14/15	1	NM_024537.4	P1

Frequencies

GnomAD3 genomes AF: 0.00157 AC: 239 AN: 152242 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00997

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00147 AC: 300 AN: 203930 Hom.: 1 AF XY: 0.00137 AC XY: 151 AN XY: 110192

Gnomad AFR exome AF: 0.000413

Gnomad AMR exome AF: 0.000591

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000651

Gnomad SAS exome AF: 0.000190

Gnomad FIN exome AF: 0.00885

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.000951

GnomAD4 exome AF: 0.00107 AC: 1539 AN: 1433068 Hom.: 6 Cov.: 33 AF XY: 0.00105 AC XY: 744 AN XY: 710536

Gnomad4 AFR exome AF: 0.000243

Gnomad4 AMR exome AF: 0.000510

Gnomad4 ASJ exome AF: 0.0000783

Gnomad4 EAS exome AF: 0.0000525

Gnomad4 SAS exome AF: 0.000230

Gnomad4 FIN exome AF: 0.00876

Gnomad4 NFE exome AF: 0.000898

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00157 AC: 239 AN: 152360 Hom.: 1 Cov.: 33 AF XY: 0.00208 AC XY: 155 AN XY: 74514

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00997

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.000544

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000583 AC: 5

ExAC AF: 0.00106 AC: 128

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined oxidative phosphorylation defect type 27 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 17, 2022	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	CARS2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2020	- -

CARS2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2020

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	0.071
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Sift4G	Benign	0.18	T
Polyphen		0.026	B
Vest4		0.22
MVP		0.34
MPC		0.16
ClinPred		0.0098	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.20

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

Other links and lift over

dbSNP: rs147216443; hg19: chr13-111294754;