NM_145239.3:c.932G>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM5PP3_Moderate

The NM_145239.3(PRRT2):c.932G>A(p.Arg311Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,610,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R311P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

PRRT2
NM_145239.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.32

Publications

1 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_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_145239.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-29814385-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 404414.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRT2	NM_145239.3 link	c.932G>A	p.Arg311Gln	missense_variant	Exon 3 of 4	ENST00000358758.12	NP_660282.2	Q7Z6L0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12 link	c.932G>A	p.Arg311Gln	missense_variant	Exon 3 of 4	1	NM_145239.3	ENSP00000351608.7		Q7Z6L0-1
ENSG00000280893	ENST00000609618.2 link	n.921G>A		non_coding_transcript_exon_variant	Exon 3 of 6	5		ENSP00000476774.2		A0A0G2JLL6

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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

GnomAD2 exomes

AF:

0.00

AC:

AN:

247284

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000891

AC:

AN:

1458554

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725618

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26000

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86020

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51868

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00000810

AC:

AN:

1111082

Other (OTH)

AF:

0.0000166

AC:

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41544

American (AMR)

AF:

0.000196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.0000409

Hom.:

Bravo

AF:

0.0000491

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

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 311 of the PRRT2 protein (p.Arg311Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRRT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1059428). Invitae Evidence 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 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. This variant disrupts the p.Arg311 amino acid residue in PRRT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

not provided

Uncertain:1

Jan 08, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24594579) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;T;.;D;D;D

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

.;D;D;.;.;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.89

D;D;D;D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.4

M;.;M;M;M;M

PhyloP100

4.3

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.3

D;.;D;.;.;.

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0030

D;.;D;.;.;.

Sift4G

Pathogenic

0.0

D;.;D;.;D;.

Polyphen

1.0

D;.;D;D;D;D

Vest4

0.86

MutPred

0.73

Gain of ubiquitination at K314 (P = 0.0519);.;Gain of ubiquitination at K314 (P = 0.0519);Gain of ubiquitination at K314 (P = 0.0519);Gain of ubiquitination at K314 (P = 0.0519);Gain of ubiquitination at K314 (P = 0.0519);

MVP

0.99

MPC

0.62

ClinPred

0.98

GERP RS

3.8

PromoterAI

-0.083

Neutral

(source)

Varity_R

0.57

gMVP

0.93

Mutation Taster

=65/35

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over