NM_145239.3:c.649delC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_145239.3(PRRT2):c.649delC(p.Arg217GlufsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,475,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R217R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0019 ( 0 hom. )

Consequence

PRRT2
NM_145239.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27

Conservation

PhyloP100: 0.693

Publications

196 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: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 16-29813694-GC-G is Pathogenic according to our data. Variant chr16-29813694-GC-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.649delC	p.Arg217GlufsTer12	frameshift	Exon 2 of 4	NP_660282.2	Q7Z6L0-1
PRRT2	NM_001256442.2		c.649delC	p.Arg217GlufsTer12	frameshift	Exon 2 of 3	NP_001243371.1	Q7Z6L0-2
PRRT2	NM_001438121.1		c.649delC	p.Arg217GlufsTer12	frameshift	Exon 2 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.649delC	p.Arg217GlufsTer12	frameshift	Exon 2 of 4	ENSP00000351608.7	Q7Z6L0-1
ENSG00000280893	ENST00000609618.2	TSL:5	n.649delC		non_coding_transcript_exon	Exon 2 of 6	ENSP00000476774.2	A0A0G2JLL6
PRRT2	ENST00000567659.3	TSL:2	c.649delC	p.Arg217GlufsTer12	frameshift	Exon 2 of 3	ENSP00000456226.1	Q7Z6L0-2

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149480

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000666

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

GnomAD2 exomes

AF:

0.00529

AC:

717

AN:

135540

AF XY:

0.00554

show subpopulations

Gnomad AFR exome

AF:

0.00323

Gnomad AMR exome

AF:

0.00610

Gnomad ASJ exome

AF:

0.0102

Gnomad EAS exome

AF:

0.00527

Gnomad FIN exome

AF:

0.00271

Gnomad NFE exome

AF:

0.00503

Gnomad OTH exome

AF:

0.00592

GnomAD4 exome

AF:

0.00193

AC:

2563

AN:

1325610

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

1325

AN XY:

657646

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00242

AC:

AN:

29780

American (AMR)

AF:

0.00360

AC:

134

AN:

37228

Ashkenazi Jewish (ASJ)

AF:

0.00237

AC:

AN:

22392

East Asian (EAS)

AF:

0.00104

AC:

AN:

36578

South Asian (SAS)

AF:

0.00198

AC:

149

AN:

75322

European-Finnish (FIN)

AF:

0.000684

AC:

AN:

49702

Middle Eastern (MID)

AF:

0.00187

AC:

AN:

5346

European-Non Finnish (NFE)

AF:

0.00195

AC:

1976

AN:

1014402

Other (OTH)

AF:

0.00177

AC:

AN:

54860

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.243

Heterozygous variant carriers

419

838

1258

1677

2096

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

184

276

368

460

<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:

0.0000134

AC:

AN:

149580

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

73010

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40650

American (AMR)

AF:

0.0000665

AC:

AN:

15042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.00

AC:

AN:

5106

South Asian (SAS)

AF:

0.00

AC:

AN:

4708

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67056

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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:

0.00779

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (10)

Episodic kinesigenic dyskinesia 1 (5)

Seizures, benign familial infantile, 2 (3)

Seizures, benign familial infantile, 2;C1865926:Infantile convulsions and choreoathetosis;C4552000:Episodic kinesigenic dyskinesia 1 (3)

Benign familial neonatal-infantile seizures 1 (1)

Episodic kinesigenic dyskinesia (1)

Inborn genetic diseases (1)

Infantile convulsions and choreoathetosis (1)

PRRT2-associated paroxysmal movement disorder (1)

PRRT2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.69

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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