NM_145239.3:c.12C>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS2_Supporting

The NM_145239.3(PRRT2):c.12C>A(p.Ser4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,448,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

PRRT2
NM_145239.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0890

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13736045).

BS2

High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRT2	NM_145239.3 link	c.12C>A	p.Ser4Arg	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.12C>A	p.Ser4Arg	missense_variant	Exon 2 of 4	1	NM_145239.3	ENSP00000351608.7		Q7Z6L0-1
ENSG00000280893	ENST00000609618.2 link	n.12C>A		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000476774.2		A0A0G2JLL6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000418

AC:

AN:

239396

Hom.:

AF XY:

0.00000771

AC XY:

AN XY:

129752

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000918

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1448428

Hom.:

Cov.:

AF XY:

0.00000555

AC XY:

AN XY:

720076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000452

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Episodic kinesigenic dyskinesia

Uncertain:1

Oct 22, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals affected with PRRT2-related conditions. This variant is present in population databases (rs757148846, ExAC 0.002%). This sequence change replaces serine with arginine at codon 4 of the PRRT2 protein (p.Ser4Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

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

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.74

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

M_CAP

Benign

0.071

MetaRNN

Benign

0.14

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

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.6

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

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-4.9

.;D;N;.;.;N;.;.;N;.;.;.;.;.

REVEL

Benign

0.13

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.013

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

Polyphen

0.39, 0.74, 0.53

.;.;B;P;.;P;.;.;P;B;.;B;B;.

Vest4

0.36, 0.35, 0.32

MutPred

0.24

Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);

MVP

0.82

MPC

0.87

ClinPred

0.98

GERP RS

2.2

Varity_R

0.25

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over