rs144540943

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The ENST00000358758.12(PRRT2):c.1013T>A(p.Val338Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,594,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V338A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PRRT2
ENST00000358758.12 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.31

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 3 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity PRRT2_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in ENST00000358758.12

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3959279).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRRT2	NM_145239.3 linkuse as main transcript	c.1013T>A	p.Val338Glu	missense_variant, splice_region_variant	4/4	ENST00000358758.12	NP_660282.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12 linkuse as main transcript	c.1013T>A	p.Val338Glu	missense_variant, splice_region_variant	4/4	1	NM_145239.3	ENSP00000351608	P1	Q7Z6L0-1
MVP-DT	ENST00000569039.5 linkuse as main transcript	n.246-4455A>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000671

AC:

AN:

149012

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445674

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719626

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:

9.08e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000671

AC:

AN:

149012

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72728

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:

0.0000149

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Episodic kinesigenic dyskinesia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 11, 2022

This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 338 of the PRRT2 protein (p.Val338Glu). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1304099). This variant has not been reported in the literature in individuals affected with PRRT2-related conditions. This variant is not present in population databases (gnomAD no frequency). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 16, 2019

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.0082

T;.;T;T;T

Eigen

Benign

0.18

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.25

.;T;.;.;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.40

T;T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.90

L;.;L;L;L

MutationTaster

Benign

0.98

D;D;N

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.67

N;N;.;.;.

REVEL

Uncertain

0.38

Sift

Uncertain

0.0010

D;D;.;.;.

Sift4G

Uncertain

0.015

D;D;.;D;.

Polyphen

0.98

D;D;D;D;D

Vest4

0.62

MutPred

0.43

Gain of disorder (P = 0.0028);.;Gain of disorder (P = 0.0028);Gain of disorder (P = 0.0028);Gain of disorder (P = 0.0028);

MVP

0.88

MPC

0.38

ClinPred

0.60

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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