rs140082252

Positions:

• chr13-110683120-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.586G>A​(p.Asp196Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,595,142 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts 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. D196H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (51 hom.)
• Consequence: CARS2 NM_024537.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.67

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=0.01248005).
• BP6: Variant 13-110683120-C-T is Benign according to our data. Variant chr13-110683120-C-T is described in ClinVar as [Benign]. Clinvar id is 383497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00137 (209/152238) while in subpopulation SAS AF= 0.0166 (80/4828). AF 95% confidence interval is 0.0136. There are 2 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARS2	NM_024537.4	c.586G>A	p.Asp196Asn	missense_variant	6/15	ENST00000257347.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARS2	ENST00000257347.9	c.586G>A	p.Asp196Asn	missense_variant	6/15	1	NM_024537.4	P1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152120 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00348 AC: 819 AN: 235382 Hom.: 18 AF XY: 0.00430 AC XY: 549 AN XY: 127792

Gnomad AFR exome AF: 0.0000659

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.0000602

Gnomad SAS exome AF: 0.0191

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000579

Gnomad OTH exome AF: 0.00268

GnomAD4 exome AF: 0.00180 AC: 2598 AN: 1442904 Hom.: 51 Cov.: 30 AF XY: 0.00239 AC XY: 1715 AN XY: 717370

Gnomad4 AFR exome AF: 0.0000621

Gnomad4 AMR exome AF: 0.000194

Gnomad4 ASJ exome AF: 0.0191

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.0191

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000277

Gnomad4 OTH exome AF: 0.00266

GnomAD4 genome AF: 0.00137 AC: 209 AN: 152238 Hom.: 2 Cov.: 33 AF XY: 0.00172 AC XY: 128 AN XY: 74460

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00136 Hom.: 1

Bravo AF: 0.000956

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00370 AC: 449

Asia WGS AF: 0.00779 AC: 27 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

Oct 05, 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 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.18
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		0.97	D
Vest4		0.38
MVP		0.60
MPC		0.36
ClinPred		0.049	T
GERP RS		5.2
Varity_R		0.36
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs140082252; hg19: chr13-111335467;