NM_145239.3:c.1013T>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_145239.3(PRRT2):c.1013T>C(p.Val338Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,594,682 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V338L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

PRRT2
NM_145239.3 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 1.31

Publications

6 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1013017).

BP6

Variant 16-29814628-T-C is Benign according to our data. Variant chr16-29814628-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197379.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145239.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRRT2	NM_145239.3	MANE Select	c.1013T>C	p.Val338Ala	missense splice_region	Exon 4 of 4	NP_660282.2	Q7Z6L0-1
PRRT2	NM_001256442.2		c.1175T>C	p.Val392Ala	missense	Exon 3 of 3	NP_001243371.1	Q7Z6L0-2
PRRT2	NM_001438121.1		c.1175T>C	p.Val392Ala	missense	Exon 3 of 3	NP_001425050.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRRT2	ENST00000358758.12	TSL:1 MANE Select	c.1013T>C	p.Val338Ala	missense splice_region	Exon 4 of 4	ENSP00000351608.7	Q7Z6L0-1
ENSG00000280893	ENST00000609618.2	TSL:5	n.1001+163T>C		intron	N/A	ENSP00000476774.2	A0A0G2JLL6
PRRT2	ENST00000567659.3	TSL:2	c.1175T>C	p.Val392Ala	missense	Exon 3 of 3	ENSP00000456226.1	Q7Z6L0-2

Frequencies

GnomAD3 genomes

AF:

0.000221

AC:

AN:

149012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000982

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

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:

0.000401

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000249

AC:

AN:

248500

AF XY:

0.000231

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000475

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000291

AC:

420

AN:

1445670

Hom.:

Cov.:

AF XY:

0.000293

AC XY:

211

AN XY:

719622

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

32846

American (AMR)

AF:

0.000204

AC:

AN:

44122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25254

East Asian (EAS)

AF:

0.00

AC:

AN:

38488

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86030

European-Finnish (FIN)

AF:

0.0000382

AC:

AN:

52410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.000354

AC:

390

AN:

1101582

Other (OTH)

AF:

0.000236

AC:

AN:

59248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000221

AC:

AN:

149012

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

AN XY:

72728

show subpopulations

African (AFR)

AF:

0.0000982

AC:

AN:

40744

American (AMR)

AF:

0.000133

AC:

AN:

15000

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

4728

South Asian (SAS)

AF:

0.00

AC:

AN:

4402

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.000401

AC:

AN:

67248

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000284

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000264

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000476

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Episodic kinesigenic dyskinesia (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0025

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.054

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.24

M_CAP

Benign

0.080

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.2

PhyloP100

1.3

PrimateAI

Uncertain

0.69

PROVEAN

Benign

0.58

REVEL

Benign

0.16

Sift

Benign

0.095

Sift4G

Uncertain

0.045

Polyphen

0.64

Vest4

0.43

MVP

0.89

MPC

0.29

ClinPred

0.023

GERP RS

3.7

PromoterAI

0.012

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.050

gMVP

0.21

Mutation Taster

=68/32

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over