16-29813694-GCCC-GCC

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV000242402: Published functional studies in transfected HEK cells demonstrate a damaging effect as this variant results in a protein that fails to target to the cell membrane (Liu et al., 2016)" and additional evidence is available in 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: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (0 hom.)
• Consequence: PRRT2 NM_145239.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27
• Conservation: PhyloP100: 0.693
• Publications: 202 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 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000242402: Published functional studies in transfected HEK cells demonstrate a damaging effect as this variant results in a protein that fails to target to the cell membrane (Liu et al., 2016);; SCV005621813: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID 37793168); SCV006080903: "functional studies show a deterious effect of the variant in the protein function." (PMID: 27172900)
• 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

Sel.	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

Sel.	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: 2 AN: 149480 Hom.: 0 Cov.: 31

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

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.: 0 Cov.: 33 AF XY: 0.00201 AC XY: 1325 AN XY: 657646

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

African (AFR) AF: 0.00242 AC: 72 AN: 29780

American (AMR) AF: 0.00360 AC: 134 AN: 37228

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 53 AN: 22392

East Asian (EAS) AF: 0.00104 AC: 38 AN: 36578

South Asian (SAS) AF: 0.00198 AC: 149 AN: 75322

European-Finnish (FIN) AF: 0.000684 AC: 34 AN: 49702

Middle Eastern (MID) AF: 0.00187 AC: 10 AN: 5346

European-Non Finnish (NFE) AF: 0.00195 AC: 1976 AN: 1014402

Other (OTH) AF: 0.00177 AC: 97 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.

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 149580 Hom.: 0 Cov.: 31 AF XY: 0.0000274 AC XY: 2 AN XY: 73010

African (AFR) AF: 0.00 AC: 0 AN: 40650

American (AMR) AF: 0.0000665 AC: 1 AN: 15042

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4708

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: 0.0000149 AC: 1 AN: 67056

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00779 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	not provided (10)
5	-	-	Episodic kinesigenic dyskinesia 1 (5)
3	-	-	Seizures, benign familial infantile, 2 (3)
3	-	-	Seizures, benign familial infantile, 2;C1865926:Infantile convulsions and choreoathetosis;C4552000:Episodic kinesigenic dyskinesia 1 (3)
1	-	-	Benign familial neonatal-infantile seizures 1 (1)
1	-	-	Episodic kinesigenic dyskinesia (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Infantile convulsions and choreoathetosis (1)
1	-	-	PRRT2-associated paroxysmal movement disorder (1)
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)

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

Other links and lift over

dbSNP: rs587778771; hg19: chr16-29825015; COSMIC: COSV54881823; COSMIC: COSV54881823;