rs141996297

Positions:

• chr13-110645957-G-A

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.1317+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00706 in 1,610,366 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (63 hom.)
• Consequence: CARS2 NM_024537.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.365

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]

CARS2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 13-110645957-G-A is Benign according to our data. Variant chr13-110645957-G-A is described in ClinVar as [Benign]. Clinvar id is 382608.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 = 0.00585 (891/152316) while in subpopulation SAS AF= 0.0108 (52/4832). AF 95% confidence interval is 0.00843. There are 6 homozygotes in gnomad4. There are 425 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARS2	NM_024537.4	c.1317+10C>T		intron_variant		ENST00000257347.9	NP_078813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARS2	ENST00000257347.9	c.1317+10C>T		intron_variant		1	NM_024537.4	ENSP00000257347.4

Frequencies

GnomAD3 genomes AF: 0.00587 AC: 893 AN: 152198 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00767

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00747 AC: 1842 AN: 246726 Hom.: 9 AF XY: 0.00806 AC XY: 1076 AN XY: 133460

Gnomad AFR exome AF: 0.00100

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.0307

Gnomad EAS exome AF: 0.000500

Gnomad SAS exome AF: 0.0129

Gnomad FIN exome AF: 0.00190

Gnomad NFE exome AF: 0.00831

Gnomad OTH exome AF: 0.00820

GnomAD4 exome AF: 0.00719 AC: 10479 AN: 1458050 Hom.: 63 Cov.: 30 AF XY: 0.00752 AC XY: 5453 AN XY: 725350

Gnomad4 AFR exome AF: 0.000813

Gnomad4 AMR exome AF: 0.00368

Gnomad4 ASJ exome AF: 0.0311

Gnomad4 EAS exome AF: 0.000203

Gnomad4 SAS exome AF: 0.0117

Gnomad4 FIN exome AF: 0.00187

Gnomad4 NFE exome AF: 0.00699

Gnomad4 OTH exome AF: 0.00860

GnomAD4 genome AF: 0.00585 AC: 891 AN: 152316 Hom.: 6 Cov.: 32 AF XY: 0.00571 AC XY: 425 AN XY: 74486

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00767

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00808 Hom.: 4

Bravo AF: 0.00628

Asia WGS AF: 0.00318 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.4
DANN	Benign	0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs141996297; hg19: chr13-111298304;