13-110683120-C-T

Variant names:

• chr13-110683120-C-T
• rs140082252
• NM_024537.4:c.586G>A

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.586G>A​(p.Asp196Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,595,142 control chromosomes in the GnomAD database, including 53 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. D196H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (51 hom.)
• Consequence: CARS2 NM_024537.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.67
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), 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=0.01248005).
• BP6: Variant 13-110683120-C-T is Benign according to our data. Variant chr13-110683120-C-T is described in ClinVar as Benign. ClinVar VariationId is 383497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0018 (2598/1442904) while in subpopulation SAS AF = 0.0191 (1600/83600). AF 95% confidence interval is 0.0184. There are 51 homozygotes in GnomAdExome4. There are 1715 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.586G>A	p.Asp196Asn	missense	Exon 6 of 15	NP_078813.1
	CARS2	NM_001352253.3		c.586G>A	p.Asp196Asn	missense	Exon 6 of 9	NP_001339182.1
	CARS2	NM_001352252.2		c.-201G>A		5_prime_UTR	Exon 7 of 16	NP_001339181.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS2	ENST00000257347.9	TSL:1 MANE Select	c.586G>A	p.Asp196Asn	missense	Exon 6 of 15	ENSP00000257347.4
	CARS2	ENST00000939453.1		c.586G>A	p.Asp196Asn	missense	Exon 6 of 15	ENSP00000609512.1
	CARS2	ENST00000890914.1		c.580G>A	p.Asp194Asn	missense	Exon 6 of 15	ENSP00000560973.1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152120 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00348 AC: 819 AN: 235382 AF XY: 0.00430

Gnomad AFR exome AF: 0.0000659

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.0000602

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000579

Gnomad OTH exome AF: 0.00268

GnomAD4 exome AF: 0.00180 AC: 2598 AN: 1442904 Hom.: 51 Cov.: 30 AF XY: 0.00239 AC XY: 1715 AN XY: 717370

African (AFR) AF: 0.0000621 AC: 2 AN: 32232

American (AMR) AF: 0.000194 AC: 8 AN: 41214

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 491 AN: 25732

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38350

South Asian (SAS) AF: 0.0191 AC: 1600 AN: 83600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53082

Middle Eastern (MID) AF: 0.00666 AC: 32 AN: 4802

European-Non Finnish (NFE) AF: 0.000277 AC: 306 AN: 1104416

Other (OTH) AF: 0.00266 AC: 158 AN: 59476

GnomAD4 genome AF: 0.00137 AC: 209 AN: 152238 Hom.: 2 Cov.: 33 AF XY: 0.00172 AC XY: 128 AN XY: 74460

African (AFR) AF: 0.0000723 AC: 3 AN: 41518

American (AMR) AF: 0.000523 AC: 8 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68012

Other (OTH) AF: 0.00190 AC: 4 AN: 2104

Alfa AF: 0.00162 Hom.: 8

Bravo AF: 0.000956

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00370 AC: 449

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	0.16
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.18
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		0.97	D
Vest4		0.38
MVP		0.60
MPC		0.36
ClinPred		0.049	T
GERP RS		5.2
Varity_R		0.36
gMVP		0.85
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs140082252; hg19: chr13-111335467;