NM_152268.4:c.*217G>A

Variant names:

• chr1-54757517-C-T
• rs2240396
• NM_152268.4:c.*217G>A

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.*217G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 504,458 control chromosomes in the GnomAD database, including 14,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3957 hom., cov: 32)
  • Exomes 𝑓: 0.22 (10424 hom.)
• Consequence: PARS2 NM_152268.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.16
• Publications: 7 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 (BayesDel_noAF=-0.9).
• BP6: Variant 1-54757517-C-T is Benign according to our data. Variant chr1-54757517-C-T is described in ClinVar as Benign. ClinVar VariationId is 1265293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.572 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.*217G>A		3_prime_UTR	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.*217G>A		3_prime_UTR	Exon 2 of 2	ENSP00000360327.3	Q7L3T8
	PARS2	ENST00000887740.1		c.*217G>A		3_prime_UTR	Exon 2 of 2	ENSP00000557799.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32008 AN: 152006 Hom.: 3950 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.207

GnomAD4 exome AF: 0.217 AC: 76313 AN: 352334 Hom.: 10424 Cov.: 3 AF XY: 0.217 AC XY: 39830 AN XY: 183426

African (AFR) AF: 0.186 AC: 1905 AN: 10244

American (AMR) AF: 0.339 AC: 4077 AN: 12040

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 2386 AN: 11622

East Asian (EAS) AF: 0.544 AC: 13874 AN: 25516

South Asian (SAS) AF: 0.237 AC: 6672 AN: 28136

European-Finnish (FIN) AF: 0.179 AC: 4297 AN: 24012

Middle Eastern (MID) AF: 0.196 AC: 320 AN: 1636

European-Non Finnish (NFE) AF: 0.175 AC: 38131 AN: 217938

Other (OTH) AF: 0.219 AC: 4651 AN: 21190

GnomAD4 genome AF: 0.211 AC: 32041 AN: 152124 Hom.: 3957 Cov.: 32 AF XY: 0.215 AC XY: 16004 AN XY: 74370

African (AFR) AF: 0.183 AC: 7579 AN: 41494

American (AMR) AF: 0.295 AC: 4506 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 662 AN: 3472

East Asian (EAS) AF: 0.589 AC: 3044 AN: 5164

South Asian (SAS) AF: 0.259 AC: 1245 AN: 4808

European-Finnish (FIN) AF: 0.181 AC: 1922 AN: 10596

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12325 AN: 67996

Other (OTH) AF: 0.208 AC: 440 AN: 2114

Alfa AF: 0.197 Hom.: 2838

Bravo AF: 0.228

Asia WGS AF: 0.405 AC: 1407 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.39
DANN	Benign	0.40
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs2240396; hg19: chr1-55223190;