rs387907128

Variant names:

• chr16-29813850-C-T
• rs387907128
• NM_145239.3:c.796C>T
• PRRT2 p.Arg266Trp

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_145239.3(PRRT2):​c.796C>T​(p.Arg266Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,630 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R266Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 1.83
• Publications: 10 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: Uncertain_significance. The variant received 1 ACMG points.

• PP5: Variant 16-29813850-C-T is Pathogenic according to our data. Variant chr16-29813850-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31177.

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.796C>T	p.Arg266Trp	missense	Exon 2 of 4	NP_660282.2	Q7Z6L0-1
	PRRT2	NM_001256442.2		c.796C>T	p.Arg266Trp	missense	Exon 2 of 3	NP_001243371.1	Q7Z6L0-2
	PRRT2	NM_001438121.1		c.796C>T	p.Arg266Trp	missense	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.796C>T	p.Arg266Trp	missense	Exon 2 of 4	ENSP00000351608.7	Q7Z6L0-1
	ENSG00000280893	ENST00000609618.2	TSL:5	n.796C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000476774.2	A0A0G2JLL6
	PRRT2	ENST00000567659.3	TSL:2	c.796C>T	p.Arg266Trp	missense	Exon 2 of 3	ENSP00000456226.1	Q7Z6L0-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251012 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461494 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727070

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111790

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00000497 Hom.: 0

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Episodic kinesigenic dyskinesia 1 (2)
-	1	-	Episodic kinesigenic dyskinesia (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.045
Eigen_PC	Benign	-0.088
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.022	D
Varity_R		0.72
gMVP		0.86
Mutation Taster		=6/94	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs387907128;

hg19: chr16-29825171;