rs201758363

Positions:

• chr13-110683135-CTG-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BS1 BS2

The NM_024537.4(CARS2):​c.572-3_572-2del variant causes a splice acceptor, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.00161 in 1,576,954 control chromosomes in the GnomAD database, including 41 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (18 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (23 hom.)
• Consequence: CARS2 NM_024537.4 splice_acceptor, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.27

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 -14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04896755 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.9, offset of 0 (no position change), new splice context is: tcataattgtctttataaAGgca. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 13-110683135-CTG-C is Benign according to our data. Variant chr13-110683135-CTG-C is described in ClinVar as [Benign]. Clinvar id is 421531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110683135-CTG-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00894 (1361/152320) while in subpopulation AFR AF= 0.0311 (1293/41558). AF 95% confidence interval is 0.0297. There are 18 homozygotes in gnomad4. There are 632 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARS2	NM_024537.4	c.572-3_572-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000257347.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARS2	ENST00000257347.9	c.572-3_572-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_024537.4	P1

Frequencies

GnomAD3 genomes AF: 0.00895 AC: 1362 AN: 152202 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00222 AC: 499 AN: 224320 Hom.: 6 AF XY: 0.00158 AC XY: 193 AN XY: 122078

Gnomad AFR exome AF: 0.0304

Gnomad AMR exome AF: 0.00170

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000190

Gnomad OTH exome AF: 0.000755

GnomAD4 exome AF: 0.000823 AC: 1173 AN: 1424634 Hom.: 23 AF XY: 0.000710 AC XY: 502 AN XY: 707486

Gnomad4 AFR exome AF: 0.0310

Gnomad4 AMR exome AF: 0.00200

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000615

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000137

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00894 AC: 1361 AN: 152320 Hom.: 18 Cov.: 33 AF XY: 0.00849 AC XY: 632 AN XY: 74482

Gnomad4 AFR AF: 0.0311

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00473 Hom.: 2

Bravo AF: 0.0103

Asia WGS AF: 0.00144 AC: 5 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

Aug 09, 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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.41		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201758363; hg19: chr13-111335482;