13-110641548-AT-ATT

Variant names:

• chr13-110641548-A-AT
• rs575601185
• NM_024537.4:c.1683dupA

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_Moderate BP6 BS2

The NM_024537.4(CARS2):​c.1683dupA​(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:3 B:3
• Conservation: PhyloP100: -0.0610
• Publications: 6 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, G2P, Laboratory for Molecular Medicine
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00708 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• 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 VariationId is 475625.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS2	NM_024537.4	MANE Select	c.1683dupA	p.Ser562IlefsTer36	frameshift	Exon 15 of 15	NP_078813.1	Q9HA77
	CARS2	NM_001352252.2		c.897dupA	p.Ser300IlefsTer36	frameshift	Exon 16 of 16	NP_001339181.1
	CARS2	NR_147941.1		n.1767dupA		non_coding_transcript_exon	Exon 17 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS2	ENST00000257347.9	TSL:1 MANE Select	c.1683dupA	p.Ser562IlefsTer36	frameshift	Exon 15 of 15	ENSP00000257347.4	Q9HA77
	CARS2	ENST00000939453.1		c.1827dupA	p.Ser610IlefsTer36	frameshift	Exon 15 of 15	ENSP00000609512.1
	CARS2	ENST00000890914.1		c.1677dupA	p.Ser560IlefsTer36	frameshift	Exon 15 of 15	ENSP00000560973.1

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

GnomAD2 exomes AF: 0.00175 AC: 439 AN: 251478 AF XY: 0.00171

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 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

African (AFR) AF: 0.000568 AC: 19 AN: 33478

American (AMR) AF: 0.000850 AC: 38 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86256

European-Finnish (FIN) AF: 0.000749 AC: 40 AN: 53392

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00430 AC: 4776 AN: 1111556

Other (OTH) AF: 0.00243 AC: 147 AN: 60376

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

African (AFR) AF: 0.000722 AC: 30 AN: 41534

American (AMR) AF: 0.000850 AC: 13 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00371 AC: 252 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.00195

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00344

EpiControl AF: 0.00279

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	1	Combined oxidative phosphorylation defect type 27 (2)
-	-	1	CARS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.061
Mutation Taster		=164/36	disease causing (ClinVar)

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: rs575601185; hg19: chr13-111293895; COSMIC: COSV57284301; COSMIC: COSV57284301;