rs587778771

chr16-29813694-GC-Gchr16-29813694-GC-GCCchr16-29813694-GC-GCCC

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 31)
• Consequence: PRRT2 NM_145239.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 0.693

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant; Number of alleles below threshold, gnomad allele frequency = 0.0000134 (2/149480) while in subpopulation AMR AF= 0.0000666 (1/15022). AF 95% confidence interval is 0. There are 0 homozygotes in gnomad. There are 2 alleles in male gnomad subpopulation. Median coverage is 31. This position pass quality control queck.
• 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
PRRT2	NM_145239.3	c.649del	p.Arg217GlufsTer12	frameshift_variant	2/4	ENST00000358758.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRRT2	ENST00000358758.12	c.649del	p.Arg217GlufsTer12	frameshift_variant	2/4	1	NM_145239.3	P1
MVP-DT	ENST00000569039.5	n.246-3522del		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149480 Hom.: 0 Cov.: 31

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 AF XY: 0.00201 AC XY: 1325 AN XY: 657646

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

Alfa AF: 0.00779 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK:

Submissions by phenotype

not provided Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2020	Common 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, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	PerkinElmer Genomics	Mar 04, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Episodic kinesigenic dyskinesia 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 10, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 08, 2018	This 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 submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based 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 -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	-	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. -

PRRT2-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, PreventionGenetics

Jan 05, 2023

The 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 submitter

clinical testing

Invitae

Oct 14, 2022

This 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 submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The 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; Méneret, 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 submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 18, 2022

- -

Infantile convulsions and choreoathetosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine

-

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

Other links and lift over

dbSNP: rs587778771; hg19: chr16-29825015;