rs141996297

Variant names:

• chr13-110645957-G-A
• rs141996297
• NM_024537.4:c.1317+10C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong 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 Likely 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation defect type 27

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine, G2P
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 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/Likely_benign. ClinVar VariationId is 382608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARS2	NM_024537.4	c.1317+10C>T		intron_variant	Intron 12 of 14	ENST00000257347.9	NP_078813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARS2	ENST00000257347.9	c.1317+10C>T		intron_variant	Intron 12 of 14	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

GnomAD2 exomes AF: 0.00747 AC: 1842 AN: 246726 AF XY: 0.00806

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 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

African (AFR) AF: 0.000813 AC: 27 AN: 33216

American (AMR) AF: 0.00368 AC: 162 AN: 44006

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 809 AN: 25998

East Asian (EAS) AF: 0.000203 AC: 8 AN: 39378

South Asian (SAS) AF: 0.0117 AC: 1004 AN: 85688

European-Finnish (FIN) AF: 0.00187 AC: 100 AN: 53364

Middle Eastern (MID) AF: 0.0156 AC: 89 AN: 5712

European-Non Finnish (NFE) AF: 0.00699 AC: 7762 AN: 1110446

Other (OTH) AF: 0.00860 AC: 518 AN: 60242

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

African (AFR) AF: 0.00137 AC: 57 AN: 41580

American (AMR) AF: 0.00575 AC: 88 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3470

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5160

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4832

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00767 AC: 522 AN: 68022

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.00787 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

Feb 11, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.4
DANN	Benign	0.33
PhyloP100		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs141996297; hg19: chr13-111298304;