chr13-110683132-T-C

Variant names:

• chr13-110683132-T-C
• rs150286306
• NM_024537.4:c.574A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_024537.4(CARS2):​c.574A>G​(p.Asn192Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000713 in 1,580,076 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N192S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00071 (1 hom.)
• Consequence: CARS2 NM_024537.4 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.73
• Publications: 2 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.037050575).
• BP6: Variant 13-110683132-T-C is Benign according to our data. Variant chr13-110683132-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475632.

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.574A>G	p.Asn192Asp	missense splice_region	Exon 6 of 15	NP_078813.1	Q9HA77
	CARS2	NM_001352253.3		c.574A>G	p.Asn192Asp	missense splice_region	Exon 6 of 9	NP_001339182.1
	CARS2	NM_001352252.2		c.-213A>G		splice_region	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.574A>G	p.Asn192Asp	missense splice_region	Exon 6 of 15	ENSP00000257347.4	Q9HA77
	CARS2	ENST00000939453.1		c.574A>G	p.Asn192Asp	missense splice_region	Exon 6 of 15	ENSP00000609512.1
	CARS2	ENST00000890914.1		c.568A>G	p.Asn190Asp	missense splice_region	Exon 6 of 15	ENSP00000560973.1

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

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: 0.00119

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000673 AC: 152 AN: 225926 AF XY: 0.000626

Gnomad AFR exome AF: 0.000137

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000867

Gnomad OTH exome AF: 0.00168

GnomAD4 exome AF: 0.000707 AC: 1009 AN: 1427834 Hom.: 1 Cov.: 28 AF XY: 0.000694 AC XY: 492 AN XY: 709190

African (AFR) AF: 0.000190 AC: 6 AN: 31582

American (AMR) AF: 0.00170 AC: 65 AN: 38266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25318

East Asian (EAS) AF: 0.00 AC: 0 AN: 37688

South Asian (SAS) AF: 0.00 AC: 0 AN: 81600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52746

Middle Eastern (MID) AF: 0.000210 AC: 1 AN: 4758

European-Non Finnish (NFE) AF: 0.000817 AC: 896 AN: 1097020

Other (OTH) AF: 0.000697 AC: 41 AN: 58856

GnomAD4 genome AF: 0.000769 AC: 117 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.000766 AC XY: 57 AN XY: 74460

African (AFR) AF: 0.000241 AC: 10 AN: 41480

American (AMR) AF: 0.00150 AC: 23 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00119 AC: 81 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000973 Hom.: 2

Bravo AF: 0.000759

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000527 AC: 64

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Combined oxidative phosphorylation defect type 27 (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.84	N
PhyloP100		2.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.10
Sift	Benign	0.22	T
Sift4G	Benign	0.18	T
Polyphen		0.0050	B
Vest4		0.34
MVP		0.36
MPC		0.20
ClinPred		0.091	T
GERP RS		4.0
Varity_R		0.29
gMVP		0.69
Mutation Taster		=98/2	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: rs150286306; hg19: chr13-111335479; COSMIC: COSV57286027; COSMIC: COSV57286027;