16-29813694-GCCC-GCCCC

Variant names:

• chr16-29813694-G-GC
• rs587778771
• NM_145239.3:c.649dupC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_145239.3(PRRT2):​c.649dupC​(p.Arg217ProfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000664 in 1,502,392 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 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00072 (0 hom.)
• Consequence: PRRT2 NM_145239.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:78 O:3
• Conservation: PhyloP100: 0.693
• Publications: 196 publications found

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]

ENSG00000280893 (HGNC:):

MVP-DT (HGNC:56029): (MVP divergent transcript)

ACMG classification

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-G-GC is Pathogenic according to our data. Variant chr16-29813694-G-GC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 65758.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRRT2	NM_145239.3	MANE Select	c.649dupC	p.Arg217ProfsTer8	frameshift	Exon 2 of 4	NP_660282.2	Q7Z6L0-1
	PRRT2	NM_001256442.2		c.649dupC	p.Arg217ProfsTer8	frameshift	Exon 2 of 3	NP_001243371.1	Q7Z6L0-2
	PRRT2	NM_001438121.1		c.649dupC	p.Arg217ProfsTer8	frameshift	Exon 2 of 3	NP_001425050.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRRT2	ENST00000358758.12	TSL:1 MANE Select	c.649dupC	p.Arg217ProfsTer8	frameshift	Exon 2 of 4	ENSP00000351608.7	Q7Z6L0-1
	ENSG00000280893	ENST00000609618.2	TSL:5	n.649dupC		non_coding_transcript_exon	Exon 2 of 6	ENSP00000476774.2	A0A0G2JLL6
	PRRT2	ENST00000567659.3	TSL:2	c.649dupC	p.Arg217ProfsTer8	frameshift	Exon 2 of 3	ENSP00000456226.1	Q7Z6L0-2

Frequencies

GnomAD3 genomes AF: 0.000147 AC: 22 AN: 149498 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000665

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00374 AC: 507 AN: 135540 AF XY: 0.00305

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.00291

Gnomad ASJ exome AF: 0.00499

Gnomad EAS exome AF: 0.00188

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00470

Gnomad OTH exome AF: 0.00405

GnomAD4 exome AF: 0.000721 AC: 975 AN: 1352792 Hom.: 0 Cov.: 33 AF XY: 0.000694 AC XY: 466 AN XY: 671036

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

African (AFR) AF: 0.000789 AC: 24 AN: 30432

American (AMR) AF: 0.00124 AC: 47 AN: 37946

Ashkenazi Jewish (ASJ) AF: 0.000614 AC: 14 AN: 22796

East Asian (EAS) AF: 0.000430 AC: 16 AN: 37244

South Asian (SAS) AF: 0.000651 AC: 50 AN: 76802

European-Finnish (FIN) AF: 0.00455 AC: 228 AN: 50072

Middle Eastern (MID) AF: 0.000369 AC: 2 AN: 5420

European-Non Finnish (NFE) AF: 0.000536 AC: 555 AN: 1036178

Other (OTH) AF: 0.000698 AC: 39 AN: 55902

⚠️ 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.

GnomAD4 genome AF: 0.000147 AC: 22 AN: 149600 Hom.: 0 Cov.: 31 AF XY: 0.000137 AC XY: 10 AN XY: 73018

African (AFR) AF: 0.000172 AC: 7 AN: 40652

American (AMR) AF: 0.0000664 AC: 1 AN: 15050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.000392 AC: 2 AN: 5106

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000164 AC: 11 AN: 67062

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00309 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	-	-	Episodic kinesigenic dyskinesia 1 (16)
15	-	-	Infantile convulsions and choreoathetosis (16)
14	-	-	not provided (14)
13	-	-	Seizures, benign familial infantile, 2 (14)
4	-	-	PRRT2-related disorder (4)
4	-	-	Seizures, benign familial infantile, 2;C1865926:Infantile convulsions and choreoathetosis;C4552000:Episodic kinesigenic dyskinesia 1 (4)
3	-	-	Seizure (3)
1	-	-	Convulsions (1)
1	-	-	Episodic kinesigenic dyskinesia (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neurodevelopmental delay (1)
1	-	-	Paroxysmal nonkinesigenic dyskinesia 1 (1)
1	-	-	PRRT2 insufficiency (1)
1	-	-	PRRT2-Associated Paroxysmal Movement Disorders (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.69
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587778771; hg19: chr16-29825015; COSMIC: COSV54880975; COSMIC: COSV54880975;