rs387907128

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP5

The NM_145239.3(PRRT2):c.796C>T(p.Arg266Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,630 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R266Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PRRT2
NM_145239.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 1.83

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:

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

MVP-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP5

Variant 16-29813850-C-T is Pathogenic according to our data. Variant chr16-29813850-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 31177.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2}. Variant chr16-29813850-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRRT2	NM_145239.3 linkuse as main transcript	c.796C>T	p.Arg266Trp	missense_variant	2/4	ENST00000358758.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRRT2	ENST00000358758.12 linkuse as main transcript	c.796C>T	p.Arg266Trp	missense_variant	2/4	1	NM_145239.3	P1	Q7Z6L0-1
MVP-DT	ENST00000569039.5 linkuse as main transcript	n.246-3677G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251012

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461494

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Episodic kinesigenic dyskinesia 1

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 09, 2022

Variant summary: PRRT2 c.796C>T (p.Arg266Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251012 control chromosomes (gnomAD). The variant, c.796C>T, has been reported in the literature in a family where two individuals were affected with Paroxysmal kinesigenic dyskinesia (Wang_2011), and in at least in one individual affected with epilepsy and/or neurodevelopmental disorders (Lindy_2018). These data indicate that the variant may be associated with disease. In addition, the variant was also reported to be found in population based sequencing projects, but no phenotype was provided for these individuals (Capalbo_2019, Narang_2020). In an in vitro functional study, the variant protein had an expression level similar to the wild-type, and also had normal subcellular localization (Zhao_2020); however, these data do not provide evidence for the variant's effect on protein function. One ClinVar submitter has assessed the variant since 2014: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Episodic kinesigenic dyskinesia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 30, 2023

This missense change has been observed in individuals with paroxysmal kinesigenic dyskinesia (PMID: 22120146; Invitae). This variant is present in population databases (rs387907128, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 266 of the PRRT2 protein (p.Arg266Trp). ClinVar contains an entry for this variant (Variation ID: 31177). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg266 amino acid residue in PRRT2. Other variant(s) that disrupt this residue have been observed in individuals with PRRT2-related conditions (PMID: 22120146, 26446061; Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change does not substantially affect PRRT2 function (PMID: 31124310). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRRT2 protein function. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.76

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

Eigen

Benign

0.045

Eigen_PC

Benign

-0.088

FATHMM_MKL

Benign

0.29

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.71

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.20

MutationAssessor

Uncertain

2.8

M;M;M;M;M;M;M

MutationTaster

Benign

0.79

N;N;N

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.3

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

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.022

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

Polyphen

1.0

D;D;D;D;D;D;D

Vest4

0.84

MutPred

0.42

Loss of disorder (P = 0.0291);Loss of disorder (P = 0.0291);Loss of disorder (P = 0.0291);Loss of disorder (P = 0.0291);Loss of disorder (P = 0.0291);Loss of disorder (P = 0.0291);Loss of disorder (P = 0.0291);

MVP

0.89

MPC

0.86

ClinPred

0.99

GERP RS

2.8

Varity_R

0.72

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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