13-110705916-C-T

Variant names:

• chr13-110705916-C-T
• rs199874662
• NM_024537.4:c.178G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024537.4(CARS2):​c.178G>A​(p.Gly60Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,423,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CARS2 NM_024537.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.303

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039351285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARS2	NM_024537.4	c.178G>A	p.Gly60Arg	missense_variant	Exon 1 of 15	ENST00000257347.9	NP_078813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARS2	ENST00000257347.9	c.178G>A	p.Gly60Arg	missense_variant	Exon 1 of 15	1	NM_024537.4	ENSP00000257347.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000533 AC: 1 AN: 187632 Hom.: 0 AF XY: 0.00000979 AC XY: 1 AN XY: 102106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000395

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1423476 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 705112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.2
DANN	Benign	0.84
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.025	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.43	N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.067
Sift	Benign	0.83	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.11
MutPred		0.54		Gain of MoRF binding (P = 0.0156);
MVP		0.16
MPC		0.20
ClinPred		0.031	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs199874662; hg19: chr13-111358263;