chr16-29813694-G-GC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS3PP5_Very_Strong

The NM_145239.3(PRRT2):c.649dupC(p.Arg217ProfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000664 in 1,502,392 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004020389: demonstrating that approximately 80% of mutated transcripts are degraded by nonsense-mediated decay and residual mutated transcripts yield an N-terminally truncated protein (e.g., Wu_2014). PMID:25457817" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R217R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00072 ( 0 hom. )

Consequence

PRRT2
NM_145239.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:79O:3

Conservation

PhyloP100: 0.693

Publications

202 publications found

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]

PRRT2 links:

ENSG00000280893 (HGNC:):

ENSG00000280893 links:

MVP-DT (HGNC:56029): (MVP divergent transcript)

MVP-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PS3

PS3 evidence extracted from ClinVar submissions: SCV004020389: demonstrating that approximately 80% of mutated transcripts are degraded by nonsense-mediated decay and residual mutated transcripts yield an N-terminally truncated protein (e.g., Wu_2014). PMID: 25457817; SCV005042834: Experimental studies indicate that this variant results in decreased expression and altered cellular localization of the protein Wu L, et al., 2014.; SCV004101501: Published functional studies indicate this variant results in decreased expression and altered cellular localization of the protein Wu L, et al., 2014.; SCV005088752: Functional studies suggest this variant is subject to rapid nonsense mediated decay [PMID: 25457817].; SCV000242403: Published functional studies indicate this variant results in decreased expression and altered cellular localization of the protein (Wu et al., 2014);; SCV001760953: Functional studies suggest this variant is subject to rapid nonsense mediated decay [PMID:25457817].; SCV001786591: Functional studies demonstrated absence of this truncated protein in transfected cell lines and cultured hippocampal neurons (Lee et al. 2012). Co-transfection of p.Arg217ProfsTer8 with wild-type PRRT2 demonstrated normal expression of wild-type PRRT2 and low/undetectable expression of truncated PRRT2, suggesting haploinsufficiency as the disease mechanism (Lee et al. 2012).; SCV000849074: Functional analysis demonstrated that the PRRT2 c.649dupC (p.R217Pfs*8) alteration results in an mRNA transcript that undergoes nonsense mediated decay (Wu, 2014). Any truncated mRNA transcript that is translated has been shown to mislocalize and is found in the cytoplasm rather than the plasma membrane (Chen, 2011). Other studies have found no detectable protein associated with the c.649dupC (p.R217Pfs*8) alteration (Li, 2015). Functional studies have also shown that the c.649dupC (p.R217Pfs*8) alteration results in a protein that is unable to interact with components of the SNARE complex or glutamate receptors (Li, 2015).

PP5

Variant 16-29813694-G-GC is Pathogenic according to our data. Variant chr16-29813694-G-GC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 65758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145239.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRRT2	NM_145239.3	MANE Select	c.649dupC	p.Arg217ProfsTer8	frameshift	Exon 2 of 4	NP_660282.2	Q7Z6L0-1
PRRT2	NM_001256442.2		c.649dupC	p.Arg217ProfsTer8	frameshift	Exon 2 of 3	NP_001243371.1	Q7Z6L0-2
PRRT2	NM_001438121.1		c.649dupC	p.Arg217ProfsTer8	frameshift	Exon 2 of 3	NP_001425050.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRRT2	ENST00000358758.12	TSL:1 MANE Select	c.649dupC	p.Arg217ProfsTer8	frameshift	Exon 2 of 4	ENSP00000351608.7	Q7Z6L0-1
ENSG00000280893	ENST00000609618.2	TSL:5	n.649dupC		non_coding_transcript_exon	Exon 2 of 6	ENSP00000476774.2	A0A0G2JLL6
PRRT2	ENST00000567659.3	TSL:2	c.649dupC	p.Arg217ProfsTer8	frameshift	Exon 2 of 3	ENSP00000456226.1	Q7Z6L0-2

Frequencies

GnomAD3 genomes

AF:

0.000147

AC:

AN:

149498

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000173

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000665

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000391

Gnomad SAS

AF:

0.000212

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000164

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00374

AC:

507

AN:

135540

AF XY:

0.00305

show subpopulations

Gnomad AFR exome

AF:

0.00462

Gnomad AMR exome

AF:

0.00291

Gnomad ASJ exome

AF:

0.00499

Gnomad EAS exome

AF:

0.00188

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.00470

Gnomad OTH exome

AF:

0.00405

GnomAD4 exome

AF:

0.000721

AC:

975

AN:

1352792

Hom.:

Cov.:

AF XY:

0.000694

AC XY:

466

AN XY:

671036

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000789

AC:

AN:

30432

American (AMR)

AF:

0.00124

AC:

AN:

37946

Ashkenazi Jewish (ASJ)

AF:

0.000614

AC:

AN:

22796

East Asian (EAS)

AF:

0.000430

AC:

AN:

37244

South Asian (SAS)

AF:

0.000651

AC:

AN:

76802

European-Finnish (FIN)

AF:

0.00455

AC:

228

AN:

50072

Middle Eastern (MID)

AF:

0.000369

AC:

AN:

5420

European-Non Finnish (NFE)

AF:

0.000536

AC:

555

AN:

1036178

Other (OTH)

AF:

0.000698

AC:

AN:

55902

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.321

Heterozygous variant carriers

160

240

320

400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000147

AC:

AN:

149600

Hom.:

Cov.:

AF XY:

0.000137

AC XY:

AN XY:

73018

show subpopulations

African (AFR)

AF:

0.000172

AC:

AN:

40652

American (AMR)

AF:

0.0000664

AC:

AN:

15050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.000392

AC:

AN:

5106

South Asian (SAS)

AF:

0.000212

AC:

AN:

4710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000164

AC:

AN:

67062

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00309

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Episodic kinesigenic dyskinesia 1 (16)

Infantile convulsions and choreoathetosis (16)

not provided (14)

Seizures, benign familial infantile, 2 (14)

PRRT2-related disorder (4)

Seizures, benign familial infantile, 2;C1865926:Infantile convulsions and choreoathetosis;C4552000:Episodic kinesigenic dyskinesia 1 (4)

Seizure (3)

Convulsions (1)

Episodic kinesigenic dyskinesia (1)

Inborn genetic diseases (1)

Neurodevelopmental delay (1)

Paroxysmal central nervous system disorders (1)

Paroxysmal nonkinesigenic dyskinesia 1 (1)

PRRT2 insufficiency (1)

PRRT2-Associated Paroxysmal Movement Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.69

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over