16-29813703-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_145239.3(PRRT2):c.649C>G(p.Arg217Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,426,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R217P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PRRT2
NM_145239.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.22

Publications

11 publications found

Variant links:

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]

PRRT2 links:

ENSG00000280893 (HGNC:):

ENSG00000280893 links:

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

MVP-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27299416).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRT2	NM_145239.3 link	c.649C>G	p.Arg217Gly	missense_variant	Exon 2 of 4	ENST00000358758.12	NP_660282.2	Q7Z6L0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12 link	c.649C>G	p.Arg217Gly	missense_variant	Exon 2 of 4	1	NM_145239.3	ENSP00000351608.7		Q7Z6L0-1
ENSG00000280893	ENST00000609618.2 link	n.649C>G		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000476774.2		A0A0G2JLL6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1426562

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707416

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32268

American (AMR)

AF:

0.00

AC:

AN:

40964

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23864

East Asian (EAS)

AF:

0.00

AC:

AN:

38912

South Asian (SAS)

AF:

0.00

AC:

AN:

81748

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5612

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1092724

Other (OTH)

AF:

0.00

AC:

AN:

58642

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Episodic kinesigenic dyskinesia

Uncertain:1

Aug 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 217 of the PRRT2 protein (p.Arg217Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRRT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1006059). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PRRT2 protein function with a negative predictive value of 95%. 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. -

Inborn genetic diseases

Uncertain:1

Jul 19, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.649C>G (p.R217G) alteration is located in exon 2 (coding exon 1) of the PRRT2 gene. This alteration results from a C to G substitution at nucleotide position 649, causing the arginine (R) at amino acid position 217 to be replaced by a glycine (G). Based on data from the Genome Aggregation Database (gnomAD), the PRRT2 c.649C>G alteration was not observed, with coverage at this position. This amino acid position is well conserved in available vertebrate species. The p.R217G alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0055

T;.;.;.;.;T;.;T;T

Eigen

Benign

0.10

Eigen_PC

Benign

0.058

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.80

.;.;T;T;T;.;T;.;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.27

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.81

L;L;L;.;L;L;.;L;L

PhyloP100

2.2

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.32

N;.;N;.;N;.;.;.;.

REVEL

Benign

0.27

Sift

Uncertain

0.0040

D;.;D;.;D;.;.;.;.

Sift4G

Benign

0.28

T;.;T;.;T;.;.;T;.

Polyphen

0.98

D;D;D;.;D;D;.;D;D

Vest4

0.79

MutPred

0.20

Loss of MoRF binding (P = 0.0154);Loss of MoRF binding (P = 0.0154);Loss of MoRF binding (P = 0.0154);Loss of MoRF binding (P = 0.0154);Loss of MoRF binding (P = 0.0154);Loss of MoRF binding (P = 0.0154);Loss of MoRF binding (P = 0.0154);Loss of MoRF binding (P = 0.0154);Loss of MoRF binding (P = 0.0154);

MVP

0.90

MPC

0.99

ClinPred

0.91

GERP RS

2.9

Varity_R

0.30

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over