16-29813701-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. P216H) 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

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 made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 96494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-29813701-C-T is described in Lovd as [Benign]. Variant chr16-29813701-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 6733 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.

BS2

High AC in GnomAd4 at 964 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRT2	NM_145239.3 link	c.647C>T	p.Pro216Leu	missense_variant	Exon 2 of 4	ENST00000358758.12	NP_660282.2	Q7Z6L0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12 link	c.647C>T	p.Pro216Leu	missense_variant	Exon 2 of 4	1	NM_145239.3	ENSP00000351608.7		Q7Z6L0-1
ENSG00000280893	ENST00000609618.2 link	n.647C>T		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000476774.2		A0A0G2JLL6

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

GnomAD3 exomes

AF:

0.00687

AC:

1492

AN:

217286

Hom.:

AF XY:

0.00722

AC XY:

853

AN XY:

118206

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 SAS exome

AF:

0.00339

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

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00274

Gnomad4 ASJ exome

AF:

0.000708

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00346

Gnomad4 FIN exome

AF:

0.0128

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.00634

GnomAD4 genome

AF:

0.00634

AC:

964

AN:

152056

Hom.:

Cov.:

AF XY:

0.00604

AC XY:

449

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.00412

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00395

Gnomad4 FIN

AF:

0.0130

Gnomad4 NFE

AF:

0.00971

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00508

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

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

- -

Mar 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 -

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

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

- -

Aug 27, 2015

Genetic Services Laboratory, University of Chicago

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

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

T;.;.;.;.;T;.;T;T

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.84

.;.;T;T;T;.;T;.;T

MetaRNN

Benign

0.0088

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

0.90

L;L;L;.;L;L;.;L;L

PrimateAI

Uncertain

0.58

PROVEAN

Benign

0.38

N;.;N;.;N;.;.;.;.

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

D;.;D;.;D;.;.;.;.

Sift4G

Uncertain

0.015

D;.;D;.;D;.;.;D;.

Polyphen

0.99

D;D;D;.;D;D;.;D;D

Vest4

0.32

MVP

0.98

MPC

0.86

ClinPred

0.021

GERP RS

3.9

Varity_R

0.22

gMVP

0.36

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over