chr16-29813694-G-C

Position:

chr16-29813694-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_145239.3(PRRT2):c.640G>C(p.Ala214Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000802 in 1,355,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00091 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00080 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

PRRT2
NM_145239.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.749

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008581936).

BP6

Variant 16-29813694-G-C is Benign according to our data. Variant chr16-29813694-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206687.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=4, Uncertain_significance=1}. Variant chr16-29813694-G-C is described in Lovd as [Benign].

BS2

High AC in GnomAdExome4 at 1087 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRRT2	NM_145239.3 linkuse as main transcript	c.640G>C	p.Ala214Pro	missense_variant	2/4	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.640G>C	p.Ala214Pro	missense_variant	2/4	1	NM_145239.3	ENSP00000351608	P1	Q7Z6L0-1
MVP-DT	ENST00000569039.5 linkuse as main transcript	n.246-3521C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

137

AN:

149504

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000266

Gnomad ASJ

AF:

0.000291

Gnomad EAS

AF:

0.00234

Gnomad SAS

AF:

0.00276

Gnomad FIN

AF:

0.0000969

Gnomad MID

AF:

0.00645

Gnomad NFE

AF:

0.000581

Gnomad OTH

AF:

0.000971

GnomAD3 exomes

AF:

0.00152

AC:

206

AN:

135540

Hom.:

AF XY:

0.00165

AC XY:

121

AN XY:

73520

show subpopulations

Gnomad AFR exome

AF:

0.00138

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.000680

Gnomad EAS exome

AF:

0.00527

Gnomad SAS exome

AF:

0.00391

Gnomad FIN exome

AF:

0.0000660

Gnomad NFE exome

AF:

0.000910

Gnomad OTH exome

AF:

0.000623

GnomAD4 exome

AF:

0.000802

AC:

1087

AN:

1355752

Hom.:

Cov.:

AF XY:

0.000836

AC XY:

562

AN XY:

672552

show subpopulations

Gnomad4 AFR exome

AF:

0.000787

Gnomad4 AMR exome

AF:

0.000473

Gnomad4 ASJ exome

AF:

0.000438

Gnomad4 EAS exome

AF:

0.00378

Gnomad4 SAS exome

AF:

0.00323

Gnomad4 FIN exome

AF:

0.0000798

Gnomad4 NFE exome

AF:

0.000559

Gnomad4 OTH exome

AF:

0.00105

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000909

AC:

136

AN:

149604

Hom.:

Cov.:

AF XY:

0.000876

AC XY:

AN XY:

73022

show subpopulations

Gnomad4 AFR

AF:

0.00155

Gnomad4 AMR

AF:

0.000266

Gnomad4 ASJ

AF:

0.000291

Gnomad4 EAS

AF:

0.00235

Gnomad4 SAS

AF:

0.00255

Gnomad4 FIN

AF:

0.0000969

Gnomad4 NFE

AF:

0.000582

Gnomad4 OTH

AF:

0.000962

Alfa

AF:

0.000472

Hom.:

ExAC

AF:

0.00102

AC:

123

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2020	This variant is associated with the following publications: (PMID: 23496026, 27123484, 22101681, 26598493, 24594579, 27907910, 31124310) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PRRT2: BP4, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 22, 2015	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 19, 2021

- -

Episodic kinesigenic dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2018

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. -

PRRT2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2024

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0052

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

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.75

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

M_CAP

Benign

0.024

MetaRNN

Benign

0.0086

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

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.90

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

MutationTaster

Benign

0.78

N;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.82

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

REVEL

Benign

0.21

Sift

Uncertain

0.022

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

Sift4G

Benign

0.12

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

Polyphen

1.0

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

Vest4

0.58

MVP

0.87

MPC

1.0

ClinPred

0.023

GERP RS

3.9

Varity_R

0.20

gMVP

0.21

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