chr1-54758458-T-C

Variant names:

• chr1-54758458-T-C
• rs2270004
• NM_152268.4:c.704A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1825 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18138 hom.)
• Consequence: PARS2 NM_152268.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.209
• Publications: 22 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 75

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152268.4. 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
	PARS2	NM_152268.4	MANE Select	c.704A>G	p.Asn235Ser	missense	Exon 2 of 2	NP_689481.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARS2	ENST00000371279.4	TSL:1 MANE Select	c.704A>G	p.Asn235Ser	missense	Exon 2 of 2	ENSP00000360327.3	Q7L3T8
	PARS2	ENST00000887740.1		c.704A>G	p.Asn235Ser	missense	Exon 2 of 2	ENSP00000557799.1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23224 AN: 151930 Hom.: 1823 Cov.: 32

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

GnomAD2 exomes AF: 0.156 AC: 39201 AN: 251262 AF XY: 0.160

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 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.: 34 AF XY: 0.157 AC XY: 113929 AN XY: 727188

African (AFR) AF: 0.148 AC: 4960 AN: 33478

American (AMR) AF: 0.105 AC: 4685 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2908 AN: 26136

East Asian (EAS) AF: 0.189 AC: 7491 AN: 39700

South Asian (SAS) AF: 0.191 AC: 16491 AN: 86256

European-Finnish (FIN) AF: 0.200 AC: 10700 AN: 53414

Middle Eastern (MID) AF: 0.174 AC: 1004 AN: 5766

European-Non Finnish (NFE) AF: 0.152 AC: 169345 AN: 1111920

Other (OTH) AF: 0.156 AC: 9442 AN: 60392

GnomAD4 genome AF: 0.153 AC: 23237 AN: 152048 Hom.: 1825 Cov.: 32 AF XY: 0.157 AC XY: 11657 AN XY: 74334

African (AFR) AF: 0.141 AC: 5864 AN: 41476

American (AMR) AF: 0.142 AC: 2167 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 377 AN: 3468

East Asian (EAS) AF: 0.172 AC: 885 AN: 5156

South Asian (SAS) AF: 0.184 AC: 889 AN: 4822

European-Finnish (FIN) AF: 0.213 AC: 2255 AN: 10574

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10286 AN: 67960

Other (OTH) AF: 0.163 AC: 343 AN: 2106

Alfa AF: 0.152 Hom.: 6103

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.074
DANN	Benign	0.31
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.59	N
PhyloP100		0.21
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.054
Sift	Benign	0.53	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.15
ClinPred		0.0014	T
GERP RS		-2.1
Varity_R		0.025
gMVP		0.11
Mutation Taster		=97/3	polymorphism (auto)

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: rs2270004; hg19: chr1-55224131; COSMIC: COSV64883505;