16-29814418-T-TG
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_145239.3(PRRT2):c.971dupG(p.Val325SerfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
PRRT2
NM_145239.3 frameshift
NM_145239.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.282
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0499 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-29814418-T-TG is Pathogenic according to our data. Variant chr16-29814418-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 871891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PRRT2 | ENST00000358758.12 | c.971dupG | p.Val325SerfsTer16 | frameshift_variant | Exon 3 of 4 | 1 | NM_145239.3 | ENSP00000351608.7 | ||
| ENSG00000280893 | ENST00000609618.2 | n.960dupG | non_coding_transcript_exon_variant | Exon 3 of 6 | 5 | ENSP00000476774.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1456206Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 724306
GnomAD4 exome
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3
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1456206
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35
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1
AN XY:
724306
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Episodic kinesigenic dyskinesia 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Seizures, benign familial infantile, 2 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | research | The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital | Mar 06, 2021 | - - |
Episodic kinesigenic dyskinesia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2023 | This premature translational stop signal has been observed in individual(s) with paroxysmal kinesigenic dyskinesia (PMID: 32392383). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Val325Serfs*16) in the PRRT2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the PRRT2 protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PRRT2 protein in which other variant(s) (p.Ile327Met) have been determined to be pathogenic (PMID: 2131349, 23496026, 24609974, 24886244). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 871891). This variant is also known as c.971_972insG. - |
PRRT2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 23, 2024 | The PRRT2 c.971dupG variant is predicted to result in a frameshift and premature protein termination (p.Val325Serfs*15). This variant has been reported in an individual with paroxysmal kinesigenic dyskinesia (Huang et al. 2020. PubMed ID: 32392383) and it has also been reported in an individual with infantile seizures (Table 2, Liu et al. 2021. PubMed ID: 34298581). This variant is reported in 0.00091% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in PRRT2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2018 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at