Genetic Variant PRRT2:p.Pro216Leu (chr16-29813701-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_145239.3(PRRT2):c.647C>T(p.Pro216Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00929 in 1,582,354 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P216R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0063 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0096 ( 86 hom. )

Consequence

PRRT2
NM_145239.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:14

Conservation

PhyloP100: 2.28

Publications

25 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008844793).

BP6

Variant 16-29813701-C-T is Benign according to our data. Variant chr16-29813701-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0096 (13729/1430298) while in subpopulation NFE AF = 0.0112 (12229/1095530). AF 95% confidence interval is 0.011. There are 86 homozygotes in GnomAdExome4. There are 6733 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 86 AD,AR gene

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
PRRT2	NM_145239.3	MANE Select	c.647C>T	p.Pro216Leu	missense	Exon 2 of 4	NP_660282.2
PRRT2	NM_001256442.2		c.647C>T	p.Pro216Leu	missense	Exon 2 of 3	NP_001243371.1
PRRT2	NM_001438121.1		c.647C>T	p.Pro216Leu	missense	Exon 2 of 3	NP_001425050.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRRT2	ENST00000358758.12	TSL:1 MANE Select	c.647C>T	p.Pro216Leu	missense	Exon 2 of 4	ENSP00000351608.7
ENSG00000280893	ENST00000609618.2	TSL:5	n.647C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000476774.2
PRRT2	ENST00000567659.3	TSL:2	c.647C>T	p.Pro216Leu	missense	Exon 2 of 3	ENSP00000456226.1

Frequencies

GnomAD3 genomes

AF:

0.00634

AC:

964

AN:

151936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00413

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00395

Gnomad FIN

AF:

0.0130

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00971

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00687

AC:

1492

AN:

217286

AF XY:

0.00722

show subpopulations

Gnomad AFR exome

AF:

0.00151

Gnomad AMR exome

AF:

0.00235

Gnomad ASJ exome

AF:

0.00134

Gnomad EAS exome

AF:

0.0000576

Gnomad FIN exome

AF:

0.0130

Gnomad NFE exome

AF:

0.0104

Gnomad OTH exome

AF:

0.00598

GnomAD4 exome

AF:

0.00960

AC:

13729

AN:

1430298

Hom.:

Cov.:

AF XY:

0.00949

AC XY:

6733

AN XY:

709430

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

32310

American (AMR)

AF:

0.00274

AC:

112

AN:

40930

Ashkenazi Jewish (ASJ)

AF:

0.000708

AC:

AN:

24004

East Asian (EAS)

AF:

0.00

AC:

AN:

39174

South Asian (SAS)

AF:

0.00346

AC:

284

AN:

81992

European-Finnish (FIN)

AF:

0.0128

AC:

664

AN:

51922

Middle Eastern (MID)

AF:

0.00267

AC:

AN:

5612

European-Non Finnish (NFE)

AF:

0.0112

AC:

12229

AN:

1095530

Other (OTH)

AF:

0.00634

AC:

373

AN:

58824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.601

Heterozygous variant carriers

663

1326

1988

2651

3314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

470

940

1410

1880

2350

<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:

0.00634

AC:

964

AN:

152056

Hom.:

Cov.:

AF XY:

0.00604

AC XY:

449

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

41500

American (AMR)

AF:

0.00412

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00395

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0130

AC:

138

AN:

10584

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00971

AC:

660

AN:

67950

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.543

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00431

Hom.:

Bravo

AF:

0.00538

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00254

AC:

ESP6500EA

AF:

0.00728

AC:

ExAC

AF:

0.00674

AC:

815

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 21, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PRRT2: PM5, BS1, BS2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:4

May 09, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 30, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 27, 2015

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 11, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Seizure

Uncertain:1

Diagnostic Laboratory, Strasbourg University Hospital

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Episodic kinesigenic dyskinesia

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Jul 07, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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

Benign:1

Aug 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0088

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

0.90

PhyloP100

2.3

PrimateAI

Uncertain

0.58

PROVEAN

Benign

0.38

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.015

Polyphen

0.99

Vest4

0.32

MVP

0.98

MPC

0.86

ClinPred

0.021

GERP RS

3.9

Varity_R

0.22

gMVP

0.36

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over