rs547578192

Variant names:

• chr13-110642360-G-A
• rs547578192
• NM_024537.4:c.1578C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_024537.4(CARS2):​c.1578C>T​(p.Cys526Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000277 in 1,554,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: CARS2 NM_024537.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0350
• Publications: 1 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 13-110642360-G-A is Benign according to our data. Variant chr13-110642360-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 475621.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.035 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024537.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS2	NM_024537.4	MANE Select	c.1578C>T	p.Cys526Cys	synonymous	Exon 14 of 15	NP_078813.1
	CARS2	NM_001352252.2		c.792C>T	p.Cys264Cys	synonymous	Exon 15 of 16	NP_001339181.1
	CARS2	NR_147941.1		n.1662C>T		non_coding_transcript_exon	Exon 16 of 17

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS2	ENST00000257347.9	TSL:1 MANE Select	c.1578C>T	p.Cys526Cys	synonymous	Exon 14 of 15	ENSP00000257347.4
	CARS2	ENST00000375781.9	TSL:2	n.2510C>T		non_coding_transcript_exon	Exon 5 of 6
	CARS2	ENST00000481787.6	TSL:5	n.1012C>T		non_coding_transcript_exon	Exon 9 of 10

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000801 AC: 13 AN: 162260 AF XY: 0.0000815

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000395

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000319

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000285 AC: 40 AN: 1402458 Hom.: 0 Cov.: 33 AF XY: 0.0000303 AC XY: 21 AN XY: 692162

African (AFR) AF: 0.00 AC: 0 AN: 31850

American (AMR) AF: 0.000386 AC: 14 AN: 36266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 36082

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79632

European-Finnish (FIN) AF: 0.0000205 AC: 1 AN: 48720

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.0000204 AC: 22 AN: 1080894

Other (OTH) AF: 0.0000344 AC: 2 AN: 58146

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CARS2-related disorder (1)
-	-	1	Combined oxidative phosphorylation defect type 27 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.30
DANN	Benign	0.83
PhyloP100		0.035
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs547578192; hg19: chr13-111294707; COSMIC: COSV57286856; COSMIC: COSV57286856;