rs76335820

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_145239.3(PRRT2):c.647C>A(p.Pro216His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,582,356 control chromosomes in the GnomAD database, including 3 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. P216L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00037 ( 3 hom. )

Consequence

PRRT2
NM_145239.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010031402).

BP6

Variant 16-29813701-C-A is Benign according to our data. Variant chr16-29813701-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 206689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-29813701-C-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRRT2	NM_145239.3 linkuse as main transcript	c.647C>A	p.Pro216His	missense_variant	2/4	ENST00000358758.12	NP_660282.2	Q7Z6L0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12 linkuse as main transcript	c.647C>A	p.Pro216His	missense_variant	2/4	1	NM_145239.3	ENSP00000351608.7		Q7Z6L0-1
ENSG00000280893	ENST00000609618.2 linkuse as main transcript	n.647C>A		non_coding_transcript_exon_variant	2/6	5		ENSP00000476774.2		A0A0G2JLL6

Frequencies

GnomAD3 genomes

AF:

0.000382

AC:

AN:

151936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000506

AC:

110

AN:

217286

Hom.:

AF XY:

0.000558

AC XY:

AN XY:

118206

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000653

Gnomad ASJ exome

AF:

0.00616

Gnomad EAS exome

AF:

0.000518

Gnomad SAS exome

AF:

0.00129

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000165

Gnomad OTH exome

AF:

0.000772

GnomAD4 exome

AF:

0.000368

AC:

526

AN:

1430300

Hom.:

Cov.:

AF XY:

0.000433

AC XY:

307

AN XY:

709434

show subpopulations

Gnomad4 AFR exome

AF:

0.0000310

Gnomad4 AMR exome

AF:

0.0000489

Gnomad4 ASJ exome

AF:

0.00825

Gnomad4 EAS exome

AF:

0.000230

Gnomad4 SAS exome

AF:

0.00131

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000154

Gnomad4 OTH exome

AF:

0.000578

GnomAD4 genome

AF:

0.000381

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.00117

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000648

Hom.:

Bravo

AF:

0.000287

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000372

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 01, 2017

- -

Episodic kinesigenic dyskinesia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2017

This alteration is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 14, 2022

- -

PRRT2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 29, 2020

This variant is associated with the following publications: (PMID: 31124310, 26598494, 23363396, 26598493, 25502464, 23077024) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

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

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.70

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

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.010

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

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

0.90

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

PrimateAI

Uncertain

0.56

PROVEAN

Benign

1.0

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

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.030

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

Polyphen

1.0

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

Vest4

0.30

MutPred

0.19

Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);

MVP

0.98

MPC

0.93

ClinPred

0.043

GERP RS

3.9

Varity_R

0.27

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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