chr13-110641584-A-C

Position:

• chr13-110641584-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024537.4(CARS2):​c.1648T>G​(p.Trp550Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CARS2 NM_024537.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARS2	NM_024537.4	c.1648T>G	p.Trp550Gly	missense_variant	15/15	ENST00000257347.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARS2	ENST00000257347.9	c.1648T>G	p.Trp550Gly	missense_variant	15/15	1	NM_024537.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation defect type 27 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 01, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CARS2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with glycine at codon 550 of the CARS2 protein (p.Trp550Gly). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-10	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.58		Gain of sheet (P = 0.0043);
MVP		0.59
MPC		0.94
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.74
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-111293931;