rs146773721

Positions:

• chr13-110683059-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.647G>A​(p.Gly216Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,600,186 control chromosomes in the GnomAD database, including 373 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G216R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (30 hom., cov: 33)
  • Exomes 𝑓: 0.018 (343 hom.)
• Consequence: CARS2 NM_024537.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.03

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=0.00331226).
• BP6: Variant 13-110683059-C-T is Benign according to our data. Variant chr13-110683059-C-T is described in ClinVar as [Benign]. Clinvar id is 380445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110683059-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0159 (2424/152302) while in subpopulation AMR AF= 0.0309 (472/15294). AF 95% confidence interval is 0.0286. There are 30 homozygotes in gnomad4. There are 1261 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARS2	NM_024537.4	c.647G>A	p.Gly216Glu	missense_variant	6/15	ENST00000257347.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARS2	ENST00000257347.9	c.647G>A	p.Gly216Glu	missense_variant	6/15	1	NM_024537.4	P1

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2425 AN: 152184 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.00369

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.0339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0196 AC: 4692 AN: 239186 Hom.: 81 AF XY: 0.0194 AC XY: 2514 AN XY: 129754

Gnomad AFR exome AF: 0.00293

Gnomad AMR exome AF: 0.0368

Gnomad ASJ exome AF: 0.00193

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0184

Gnomad FIN exome AF: 0.0363

Gnomad NFE exome AF: 0.0189

Gnomad OTH exome AF: 0.0166

GnomAD4 exome AF: 0.0185 AC: 26762 AN: 1447884 Hom.: 343 Cov.: 30 AF XY: 0.0184 AC XY: 13221 AN XY: 720240

Gnomad4 AFR exome AF: 0.00274

Gnomad4 AMR exome AF: 0.0363

Gnomad4 ASJ exome AF: 0.00162

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.0189

Gnomad4 FIN exome AF: 0.0341

Gnomad4 NFE exome AF: 0.0187

Gnomad4 OTH exome AF: 0.0165

GnomAD4 genome AF: 0.0159 AC: 2424 AN: 152302 Hom.: 30 Cov.: 33 AF XY: 0.0169 AC XY: 1261 AN XY: 74476

Gnomad4 AFR AF: 0.00368

Gnomad4 AMR AF: 0.0309

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0151

Gnomad4 FIN AF: 0.0339

Gnomad4 NFE AF: 0.0192

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0166 Hom.: 53

Bravo AF: 0.0154

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0195 AC: 168

ExAC AF: 0.0185 AC: 2250

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Combined oxidative phosphorylation defect type 27 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.0
DANN	Benign	0.38
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.060
Sift	Benign	0.40	T
Sift4G	Benign	0.59	T
Polyphen		0.0050	B
Vest4		0.046
MPC		0.24
ClinPred		0.00098	T
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.63

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: rs146773721; hg19: chr13-111335406;