rs142070578

Positions:

• chr13-110647166-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024537.4(CARS2):​c.1128C>T​(p.Asp376=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,612,396 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (8 hom.)
• Consequence: CARS2 NM_024537.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.466

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-110647166-G-A is Benign according to our data. Variant chr13-110647166-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.466 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00293 (446/152332) while in subpopulation NFE AF= 0.00378 (257/68026). AF 95% confidence interval is 0.0034. There are 0 homozygotes in gnomad4. There are 216 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARS2	NM_024537.4	c.1128C>T	p.Asp376=	synonymous_variant	11/15	ENST00000257347.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARS2	ENST00000257347.9	c.1128C>T	p.Asp376=	synonymous_variant	11/15	1	NM_024537.4	P1

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 446 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00378

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00232 AC: 575 AN: 247740 Hom.: 3 AF XY: 0.00226 AC XY: 303 AN XY: 134346

Gnomad AFR exome AF: 0.00232

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00270

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000693

Gnomad FIN exome AF: 0.000339

Gnomad NFE exome AF: 0.00368

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00304 AC: 4444 AN: 1460064 Hom.: 8 Cov.: 30 AF XY: 0.00292 AC XY: 2120 AN XY: 726260

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.00193

Gnomad4 ASJ exome AF: 0.00314

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000675

Gnomad4 FIN exome AF: 0.000400

Gnomad4 NFE exome AF: 0.00353

Gnomad4 OTH exome AF: 0.00287

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.00290 AC XY: 216 AN XY: 74496

Gnomad4 AFR AF: 0.00284

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00378

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00310 Hom.: 0

Bravo AF: 0.00294

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00386

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	CARS2: BP4, BP7, BS2 -

Combined oxidative phosphorylation defect type 27 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.60
DANN	Benign	0.33

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: rs142070578; hg19: chr13-111299513; COSMIC: COSV99959541; COSMIC: COSV99959541;