chr13-110641568-T-G

Position:

• chr13-110641568-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024537.4(CARS2):​c.1664A>C​(p.Gln555Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,613,518 control chromosomes in the GnomAD database, including 12,320 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (945 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11375 hom.)
• Consequence: CARS2 NM_024537.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0340

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014221072).
• BP6: Variant 13-110641568-T-G is Benign according to our data. Variant chr13-110641568-T-G is described in ClinVar as [Benign]. Clinvar id is 380143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARS2	NM_024537.4	c.1664A>C	p.Gln555Pro	missense_variant	15/15	ENST00000257347.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARS2	ENST00000257347.9	c.1664A>C	p.Gln555Pro	missense_variant	15/15	1	NM_024537.4	P1

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16490 AN: 152150 Hom.: 945 Cov.: 33

Gnomad AFR AF: 0.0623

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0602

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.123

GnomAD3 exomes AF: 0.115 AC: 28872 AN: 251450 Hom.: 1816 AF XY: 0.115 AC XY: 15659 AN XY: 135898

Gnomad AFR exome AF: 0.0617

Gnomad AMR exome AF: 0.0979

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.110

Gnomad SAS exome AF: 0.0623

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.122 AC: 178116 AN: 1461250 Hom.: 11375 Cov.: 31 AF XY: 0.121 AC XY: 87953 AN XY: 726986

Gnomad4 AFR exome AF: 0.0603

Gnomad4 AMR exome AF: 0.100

Gnomad4 ASJ exome AF: 0.123

Gnomad4 EAS exome AF: 0.0961

Gnomad4 SAS exome AF: 0.0646

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.108 AC: 16483 AN: 152268 Hom.: 945 Cov.: 33 AF XY: 0.108 AC XY: 8049 AN XY: 74456

Gnomad4 AFR AF: 0.0621

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.0605

Gnomad4 FIN AF: 0.161

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.122

Alfa AF: 0.117 Hom.: 936

Bravo AF: 0.104

TwinsUK AF: 0.126 AC: 468

ALSPAC AF: 0.123 AC: 473

ESP6500AA AF: 0.0581 AC: 256

ESP6500EA AF: 0.128 AC: 1102

ExAC AF: 0.112 AC: 13596

Asia WGS AF: 0.0860 AC: 299 AN: 3478

EpiCase AF: 0.132

EpiControl AF: 0.138

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Combined oxidative phosphorylation defect type 27 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.9
DANN	Benign	0.81
DEOGEN2	Benign	0.081	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.52	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.031
Sift	Benign	0.46	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.080
MPC		0.20
ClinPred		0.00022	T
GERP RS		-0.91
Varity_R		0.15
gMVP		0.28

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: rs1043886; hg19: chr13-111293915; COSMIC: COSV57286566; COSMIC: COSV57286566;