Genetic Variant PRRT2:p.Arg217ProfsTer13 (chr16-29813694-G-GCC) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_145239.3(PRRT2):c.648_649dupCC(p.Arg217ProfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000017 in 1,355,868 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 31)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

PRRT2
NM_145239.3 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRT2	NM_145239.3 link	c.648_649dupCC	p.Arg217ProfsTer13	frameshift_variant	Exon 2 of 4	ENST00000358758.12	NP_660282.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12 link	c.648_649dupCC	p.Arg217ProfsTer13	frameshift_variant	Exon 2 of 4	1	NM_145239.3	ENSP00000351608.7
ENSG00000280893	ENST00000609618.2 link	n.648_649dupCC		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000476774.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000590

AC:

AN:

135540

AF XY:

0.0000272

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000550

Gnomad ASJ exome

AF:

0.000227

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000827

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000170

AC:

AN:

1355868

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

672602

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30504

American (AMR)

AF:

0.00

AC:

AN:

38054

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22842

East Asian (EAS)

AF:

0.00

AC:

AN:

37316

South Asian (SAS)

AF:

0.00

AC:

AN:

76988

European-Finnish (FIN)

AF:

0.000399

AC:

AN:

50118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5424

European-Non Finnish (NFE)

AF:

0.00000289

AC:

AN:

1038610

Other (OTH)

AF:

0.00

AC:

AN:

56012

⚠️ 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: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.69

Mutation Taster

=1/199

disease causing (fs/PTC)

(source)

Splicing

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

Publications

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16-29813694-GCCC-GCCCCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over