rs200849527

chr16-29813734-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_145239.3(PRRT2):c.680G>A(p.Arg227Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,429,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R227G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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]

MVP-DT (HGNC:56029): (MVP divergent transcript)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.087020874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRRT2	NM_145239.3	c.680G>A	p.Arg227Gln	missense_variant	2/4	ENST00000358758.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRRT2	ENST00000358758.12	c.680G>A	p.Arg227Gln	missense_variant	2/4	1	NM_145239.3	P1
MVP-DT	ENST00000569039.5	n.246-3561C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000136 AC: 3 AN: 220318 Hom.: 0 AF XY: 0.0000168 AC XY: 2 AN XY: 118936

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000330

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000200

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000182 AC: 26 AN: 1429710 Hom.: 0 Cov.: 44 AF XY: 0.0000254 AC XY: 18 AN XY: 708300

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000245

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000491

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000146

Gnomad4 OTH exome AF: 0.0000680

GnomAD4 genome Cov.: 31

Alfa AF: 0.00000576 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Episodic kinesigenic dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 06, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRRT2 protein function. ClinVar contains an entry for this variant (Variation ID: 536485). This missense change has been observed in individual(s) with paroxysmal kinesigenic dyskinesia (PMID: 34825340). This variant is present in population databases (rs200849527, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 227 of the PRRT2 protein (p.Arg227Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	21
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.0043	T;.;.;.;.;T;.;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.31	N
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.087	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.81	L;L;L;.;L;L;.;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.020	N;.;N;.;N;.;.;.;.
REVEL	Benign	0.13
Sift	Uncertain	0.0050	D;.;D;.;D;.;.;.;.
Sift4G	Benign	0.38	T;.;T;.;T;.;.;T;.
Polyphen		0.99	D;D;D;.;D;D;.;D;D
Vest4		0.30
MutPred		0.21		Loss of MoRF binding (P = 0.0279);Loss of MoRF binding (P = 0.0279);Loss of MoRF binding (P = 0.0279);Loss of MoRF binding (P = 0.0279);Loss of MoRF binding (P = 0.0279);Loss of MoRF binding (P = 0.0279);Loss of MoRF binding (P = 0.0279);Loss of MoRF binding (P = 0.0279);Loss of MoRF binding (P = 0.0279);
MVP		0.83
MPC		0.84
ClinPred		0.38	T
GERP RS		2.9
Varity_R		0.088
gMVP		0.15

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: rs200849527; hg19: chr16-29825055;