rs79081036

Variant names:

• chr13-110647162-G-A
• rs79081036
• NM_024537.4:c.1132C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-110647162-G-A
• chr13-110647162-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024537.4(CARS2):​c.1132C>T​(p.Arg378Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,612,036 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R378H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (46 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (36 hom.)
• Consequence: CARS2 NM_024537.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.45
• 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, G2P, Laboratory for Molecular Medicine
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061453283).
• BP6: Variant 13-110647162-G-A is Benign according to our data. Variant chr13-110647162-G-A is described in ClinVar as Benign. ClinVar VariationId is 382065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.012 (1821/152334) while in subpopulation AFR AF = 0.0419 (1744/41582). AF 95% confidence interval is 0.0403. There are 46 homozygotes in GnomAd4. There are 817 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 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.1132C>T	p.Arg378Cys	missense	Exon 11 of 15	NP_078813.1	Q9HA77
	CARS2	NM_001352252.2		c.346C>T	p.Arg116Cys	missense	Exon 12 of 16	NP_001339181.1
	CARS2	NR_147941.1		n.1103C>T		non_coding_transcript_exon	Exon 12 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS2	ENST00000257347.9	TSL:1 MANE Select	c.1132C>T	p.Arg378Cys	missense	Exon 11 of 15	ENSP00000257347.4	Q9HA77
	CARS2	ENST00000939453.1		c.1132C>T	p.Arg378Cys	missense	Exon 11 of 15	ENSP00000609512.1
	CARS2	ENST00000890914.1		c.1126C>T	p.Arg376Cys	missense	Exon 11 of 15	ENSP00000560973.1

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1814 AN: 152216 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

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: 0.000132

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00297 AC: 734 AN: 247018 AF XY: 0.00219

Gnomad AFR exome AF: 0.0433

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000537

Gnomad OTH exome AF: 0.000829

GnomAD4 exome AF: 0.00117 AC: 1705 AN: 1459702 Hom.: 36 Cov.: 30 AF XY: 0.000985 AC XY: 715 AN XY: 726014

African (AFR) AF: 0.0435 AC: 1455 AN: 33452

American (AMR) AF: 0.00132 AC: 59 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52352

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5742

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111524

Other (OTH) AF: 0.00247 AC: 149 AN: 60316

GnomAD4 genome AF: 0.0120 AC: 1821 AN: 152334 Hom.: 46 Cov.: 33 AF XY: 0.0110 AC XY: 817 AN XY: 74494

African (AFR) AF: 0.0419 AC: 1744 AN: 41582

American (AMR) AF: 0.00327 AC: 50 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68020

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00279 Hom.: 16

Bravo AF: 0.0137

ESP6500AA AF: 0.0472 AC: 208

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00384 AC: 466

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	0.050
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.071	N
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.5
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.18
Sift	Benign	0.043	D
Sift4G	Uncertain	0.053	T
Polyphen		0.99	D
Vest4		0.53
MVP		0.57
MPC		0.58
ClinPred		0.024	T
GERP RS		4.2
PromoterAI		0.063	Neutral
Varity_R		0.12
gMVP		0.35
Mutation Taster		=92/8	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: rs79081036; hg19: chr13-111299509;