rs730882065

Positions:

• chr16-29813563-TTCTG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_145239.3(PRRT2):​c.514_517delTCTG​(p.Ser172fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRRT2 NM_145239.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.212

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:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-29813563-TTCTG-T is Pathogenic according to our data. Variant chr16-29813563-TTCTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 31169.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-29813563-TTCTG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRRT2	NM_145239.3	c.514_517delTCTG	p.Ser172fs	frameshift_variant	2/4	ENST00000358758.12	NP_660282.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12	c.514_517delTCTG	p.Ser172fs	frameshift_variant	2/4	1	NM_145239.3	ENSP00000351608.7
ENSG00000280893	ENST00000609618.2	n.514_517delTCTG		non_coding_transcript_exon_variant	2/6	5		ENSP00000476774.2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic kinesigenic dyskinesia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 20, 2011

- -

Episodic kinesigenic dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This premature translational stop signal has been observed in individual(s) with paroxysmal kinesigenic dyskinesia (PMID: 22101681). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser172Argfs*3) in the PRRT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRRT2 are known to be pathogenic (PMID: 22623405, 22744660). ClinVar contains an entry for this variant (Variation ID: 31169). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs730882065; hg19: chr16-29824884;