Menu
GeneBe

rs587778771

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_145239.3(PRRT2):c.649del(p.Arg217GlufsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,475,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A214A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0019 ( 0 hom. )

Consequence

PRRT2
NM_145239.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 0.693
Variant links:
Genes affected
PRRT2 (HGNC:30500): (proline rich transmembrane protein 2) This gene encodes a transmembrane protein containing a proline-rich domain in its N-terminal half. Studies in mice suggest that it is predominantly expressed in brain and spinal cord in embryonic and postnatal stages. Mutations in this gene are associated with episodic kinesigenic dyskinesia-1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]
MVP-DT (HGNC:56029): (MVP divergent transcript)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 16-29813694-GC-G is Pathogenic according to our data. Variant chr16-29813694-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-29813694-GC-G is described in Lovd as [Pathogenic]. Variant chr16-29813694-GC-G is described in Lovd as [Pathogenic]. Variant chr16-29813694-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PRRT2NM_145239.3 linkuse as main transcriptc.649del p.Arg217GlufsTer12 frameshift_variant 2/4 ENST00000358758.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PRRT2ENST00000358758.12 linkuse as main transcriptc.649del p.Arg217GlufsTer12 frameshift_variant 2/41 NM_145239.3 P1Q7Z6L0-1
MVP-DTENST00000569039.5 linkuse as main transcriptn.246-3522del intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0000134
AC:
2
AN:
149480
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000666
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000149
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00193
AC:
2563
AN:
1325610
Hom.:
0
Cov.:
33
AF XY:
0.00201
AC XY:
1325
AN XY:
657646
show subpopulations
Gnomad4 AFR exome
AF:
0.00242
Gnomad4 AMR exome
AF:
0.00360
Gnomad4 ASJ exome
AF:
0.00237
Gnomad4 EAS exome
AF:
0.00104
Gnomad4 SAS exome
AF:
0.00198
Gnomad4 FIN exome
AF:
0.000684
Gnomad4 NFE exome
AF:
0.00195
Gnomad4 OTH exome
AF:
0.00177
GnomAD4 genome
AF:
0.0000134
AC:
2
AN:
149580
Hom.:
0
Cov.:
31
AF XY:
0.0000274
AC XY:
2
AN XY:
73010
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000665
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000149
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00779
Hom.:
0

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:19
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:8
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 22, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 01, 2020Common pathogenic variant that accounts for approximately 4% of all pathogenic variants in the PRRT2 gene (Ebrahimi-Fakhari et al., 2015); Reported previously in unrelated individuals with PRRT2-related disorders (Meneret et al., 2012; Yang et al., 2013; Ebrahimi-Fakhari et al., 2015); Published functional studies in transfected HEK cells demonstrate a damaging effect as this variant results in a protein that fails to target to the cell membrane (Liu et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25522171, 22870186, 23077016, 26446061, 24755245, 23551744, 25060993, 24609974, 24101679, 22752065, 23165339, 24465263, 25502464, 23363396, 24370076, 25449067, 28906077, 26598493, 29655203, 31487502, 31901402, 31902651, 32369273, 27172900, 34012299, 32651081, 22744660) -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2022- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 04, 2022- -
Likely pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Episodic kinesigenic dyskinesia 1 Pathogenic:3
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 10, 2012- -
Likely pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsNov 08, 2018This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple individuals [PMID 22744660, 24755245, 25522171, 28906077, 27172900, 24370076, 25449067] -
Seizures, benign familial infantile, 2 Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The frame shift c.649del (p.Arg217GlufsTer12) variant in the PRRT2 gene has been reported previously in multiple individuals with PRRT2-related disorders (Meneret et al., 2012). This variant has been reported to segregate with PRRT2-related conditions in families (Brueckner F et al., 2014). The p.Arg217GlufsTer12 variant is reported with the allele frequency (0.4%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Arginine 217, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Arg217GlufsTer12. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterNov 11, 2019- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteFeb 02, 2022Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with PRRT2 -related disorder. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:22744660). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with PRRT2 -related disorders (ClinVar), and has been found in 20 to 45% of the patients with paroxysmal kinesigenic dyskinesia (PMID: 31722684). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
PRRT2-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 05, 2023The PRRT2 c.649delC variant is predicted to result in a frameshift and premature protein termination (p.Arg217Glufs*12). This variant is among the most frequently reported causes of PRRT2-related epilepsy, accounting for approximately 4% of affected individuals (Ebrahimi-Fakhari et al. 2015. PubMed ID: 26598493). This variant has been reported in patients with paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), and infantile convulsions with paroxysmal choreoathetosis and febrile seizures (Méneret et al. 2012. PubMed ID: 22744660; Brueckner et al. 2014. PubMed ID: 24755245; He et al. 2014. PubMed ID: 25522171; Yang et al. 2013. PubMed ID: 24370076). This variant is classified as pathogenic. -
Episodic kinesigenic dyskinesia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 19, 2024This sequence change creates a premature translational stop signal (p.Arg217Glufs*12) in the PRRT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRRT2 are known to be pathogenic (PMID: 22623405, 22744660). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with clinical features of PRRT2-related conditions (PMID: 22744660, 23077016, 24370076, 24755245, 25522171). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39752). For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 18, 2023The c.649delC (p.R217Efs*12) alteration, located in exon 2 (coding exon 1) of the PRRT2 gene, consists of a deletion of one nucleotide at position 649, causing a translational frameshift with a predicted alternate stop codon after 12 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.001% (2/149480) total alleles studied. The highest observed frequency was 0.007% (1/15022) of Latino/Admixed American alleles. This alteration was reported in several individuals and families with variable phenotypes within the spectrum of PRRT2-related paroxysmal movement disorders (Riant, 2012; M&eacute;neret, 2012; Yang, 2013; He, 2014; Brueckner, 2014; Zeng, 2018). This alteration is found in about 4% of PRRT2-related benign familial infantile epilepsy cases (Ebrahimi-Fakhari, 2015). Based on the available evidence, this alteration is classified as pathogenic. -
Seizures, benign familial infantile, 2;C1865926:Infantile convulsions and choreoathetosis;C4552000:Episodic kinesigenic dyskinesia 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 18, 2022- -
Infantile convulsions and choreoathetosis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The c.649delC pathogenic variant in the PRRT2 gene has been reported previously in multiple unrelated individuals affected with Convulsions, familial infantile, with paroxysmal choreoathetosis (Meneret et al., 2012). This variant has been reported to segregate with PRRT2-related conditions in families (Brueckner et. al., 2014) and has been reported in individuals affected with paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, hemiplegic migraine, (Meneret et al., 2012; Yang X et. al., 2013). The p.Arg217GlufsTer12 variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.4% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. This variant causes a frameshift starting with codon Arginine 217, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Arg217GlufsTer12. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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.

Other links and lift over

dbSNP: rs587778771; hg19: chr16-29825015; API