13-110641548-A-AT

Position:

• chr13-110641548-A-AT

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM4 BP6 BS1 BS2

The NM_024537.4(CARS2):​c.1683_1684insA​(p.Ser562IlefsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,613,608 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (6 hom.)
• Consequence: CARS2 NM_024537.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -0.0610

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 -7 ACMG points.

• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 602 codons.
• BP6: Variant 13-110641548-A-AT is Benign according to our data. Variant chr13-110641548-A-AT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475625.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00202 (307/152230) while in subpopulation NFE AF= 0.00371 (252/68008). AF 95% confidence interval is 0.00333. There are 0 homozygotes in gnomad4. There are 138 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.1683_1684insA	p.Ser562IlefsTer36	frameshift_variant	15/15	ENST00000257347.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARS2	ENST00000257347.9	c.1683_1684insA	p.Ser562IlefsTer36	frameshift_variant	15/15	1	NM_024537.4	P1

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00371

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00175 AC: 439 AN: 251478 Hom.: 1 AF XY: 0.00171 AC XY: 232 AN XY: 135914

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00310

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.00350 AC: 5108 AN: 1461378 Hom.: 6 Cov.: 30 AF XY: 0.00341 AC XY: 2482 AN XY: 727034

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.00430

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.00202 AC: 307 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.00185 AC XY: 138 AN XY: 74426

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00371

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00195

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00344

EpiControl AF: 0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	CARS2: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 07, 2022	PM4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2022	Frameshift variant predicted to result in protein truncation as the last 3 amino acids are replaced with 35 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge -

Combined oxidative phosphorylation defect type 27 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

CARS2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 2023

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

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: rs575601185; hg19: chr13-111293895;