rs730882124

Variant names:

• chr16-29813703-CG-C
• rs730882124
• NM_145239.3:c.650delG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001256442.2(PRRT2):​c.650delG​(p.Arg217GlnfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,426,560 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: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PRRT2 NM_001256442.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.74
• Publications: 4 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 18 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 16-29813703-CG-C is Pathogenic according to our data. Variant chr16-29813703-CG-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256442.2. 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.650delG	p.Arg217GlnfsTer12	frameshift	Exon 2 of 4	NP_660282.2
	PRRT2	NM_001256442.2		c.650delG	p.Arg217GlnfsTer12	frameshift	Exon 2 of 3	NP_001243371.1
	PRRT2	NM_001438121.1		c.650delG	p.Arg217GlnfsTer12	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.650delG	p.Arg217GlnfsTer12	frameshift	Exon 2 of 4	ENSP00000351608.7
	ENSG00000280893	ENST00000609618.2	TSL:5	n.650delG		non_coding_transcript_exon	Exon 2 of 6	ENSP00000476774.2
	PRRT2	ENST00000567659.3	TSL:2	c.650delG	p.Arg217GlnfsTer12	frameshift	Exon 2 of 3	ENSP00000456226.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1426560 Hom.: 0 Cov.: 36 AF XY: 0.00000141 AC XY: 1 AN XY: 707414

African (AFR) AF: 0.00 AC: 0 AN: 32268

American (AMR) AF: 0.00 AC: 0 AN: 40964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23864

East Asian (EAS) AF: 0.00 AC: 0 AN: 38912

South Asian (SAS) AF: 0.00 AC: 0 AN: 81748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1092722

Other (OTH) AF: 0.00 AC: 0 AN: 58642

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Seizures, benign familial infantile, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7
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: rs730882124; hg19: chr16-29825024;