rs2270004

Positions:

chr1-54758458-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152268.4(PARS2):c.704A>G(p.Asn235Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,613,830 control chromosomes in the GnomAD database, including 19,963 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.15 ( 1825 hom., cov: 32)

Exomes 𝑓: 0.16 ( 18138 hom. )

Consequence

PARS2
NM_152268.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.209

Variant links:

Genes affected

PARS2 (HGNC:30563): (prolyl-tRNA synthetase 2, mitochondrial) This gene encodes a putative member of the class II 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 proline to tRNA molecules. Mutations have been found in this gene in some patients with Alpers syndrome. [provided by RefSeq, Mar 2015]

PARS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002560705).

BP6

Variant 1-54758458-T-C is Benign according to our data. Variant chr1-54758458-T-C is described in ClinVar as [Benign]. Clinvar id is 380003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARS2	NM_152268.4 linkuse as main transcript	c.704A>G	p.Asn235Ser	missense_variant	2/2	ENST00000371279.4	NP_689481.2	Q7L3T8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARS2	ENST00000371279.4 linkuse as main transcript	c.704A>G	p.Asn235Ser	missense_variant	2/2	1	NM_152268.4	ENSP00000360327.3		Q7L3T8

Frequencies

GnomAD3 genomes

AF:

0.153

AC:

23224

AN:

151930

Hom.:

1823

Cov.:

show subpopulations

Gnomad AFR

AF:

0.141

Gnomad AMI

AF:

0.116

Gnomad AMR

AF:

0.142

Gnomad ASJ

AF:

0.109

Gnomad EAS

AF:

0.171

Gnomad SAS

AF:

0.184

Gnomad FIN

AF:

0.213

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.151

Gnomad OTH

AF:

0.164

GnomAD3 exomes

AF:

0.156

AC:

39201

AN:

251262

Hom.:

3284

AF XY:

0.160

AC XY:

21760

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.145

Gnomad AMR exome

AF:

0.0996

Gnomad ASJ exome

AF:

0.107

Gnomad EAS exome

AF:

0.163

Gnomad SAS exome

AF:

0.190

Gnomad FIN exome

AF:

0.206

Gnomad NFE exome

AF:

0.159

Gnomad OTH exome

AF:

0.160

GnomAD4 exome

AF:

0.155

AC:

227026

AN:

1461782

Hom.:

18138

Cov.:

AF XY:

0.157

AC XY:

113929

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.148

Gnomad4 AMR exome

AF:

0.105

Gnomad4 ASJ exome

AF:

0.111

Gnomad4 EAS exome

AF:

0.189

Gnomad4 SAS exome

AF:

0.191

Gnomad4 FIN exome

AF:

0.200

Gnomad4 NFE exome

AF:

0.152

Gnomad4 OTH exome

AF:

0.156

GnomAD4 genome

AF:

0.153

AC:

23237

AN:

152048

Hom.:

1825

Cov.:

AF XY:

0.157

AC XY:

11657

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.141

Gnomad4 AMR

AF:

0.142

Gnomad4 ASJ

AF:

0.109

Gnomad4 EAS

AF:

0.172

Gnomad4 SAS

AF:

0.184

Gnomad4 FIN

AF:

0.213

Gnomad4 NFE

AF:

0.151

Gnomad4 OTH

AF:

0.163

Alfa

AF:

0.150

Hom.:

2978

Bravo

AF:

0.147

TwinsUK

AF:

0.155

AC:

573

ALSPAC

AF:

0.155

AC:

597

ESP6500AA

AF:

0.141

AC:

622

ESP6500EA

AF:

0.144

AC:

1241

ExAC

AF:

0.161

AC:

19514

Asia WGS

AF:

0.167

AC:

580

AN:

3478

EpiCase

AF:

0.157

EpiControl

AF:

0.159

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 23. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2016	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.074

DANN

Benign

0.31

DEOGEN2

Benign

0.10

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.59

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.76

REVEL

Benign

0.054

Sift

Benign

0.53

Sift4G

Benign

0.60

Polyphen

0.0

Vest4

0.029

MPC

0.15

ClinPred

0.0014

GERP RS

-2.1

Varity_R

0.025

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over