rs944092875

Positions:

• chr16-29813799-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BS2_Supporting

The NM_145239.3(PRRT2):​c.745T>C​(p.Ser249Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 1,459,196 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: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.0790

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:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity PRRT2_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.20756918).
• BS2: High AC in GnomAdExome4 at 13 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/exons	MANE	Protein	UniProt
PRRT2	NM_145239.3	c.745T>C	p.Ser249Pro	missense_variant	2/4	ENST00000358758.12	NP_660282.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12	c.745T>C	p.Ser249Pro	missense_variant	2/4	1	NM_145239.3	ENSP00000351608.7
ENSG00000280893	ENST00000609618.2	n.745T>C		non_coding_transcript_exon_variant	2/6	5		ENSP00000476774.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1459196 Hom.: 0 Cov.: 43 AF XY: 0.00000689 AC XY: 5 AN XY: 725956

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic kinesigenic dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 21, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 249 of the PRRT2 protein (p.Ser249Pro). 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: 468620). 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. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Dec 17, 2022

- -

PRRT2-Associated Paroxysmal Movement Disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 14, 2023

The PRRT2 c.745T>C (p.Ser249Pro) missense variant results in the substitution of serine at amino acid position 249 with proline. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.745T>C (p.Ser249Pro) variant is classified as a variant of uncertain significance for PRRT2-associated paroxysmal movement disorders. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T;.;.;.;T;T;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.076
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.70	.;.;T;T;.;.;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.81	L;L;L;L;L;L;L
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.5	D;.;D;D;.;.;.
REVEL	Benign	0.17
Sift	Uncertain	0.0050	D;.;D;D;.;.;.
Sift4G	Uncertain	0.051	T;.;D;T;.;T;.
Polyphen		0.99	D;D;D;D;D;D;D
Vest4		0.47
MutPred		0.23		Loss of phosphorylation at S249 (P = 0.0221);Loss of phosphorylation at S249 (P = 0.0221);Loss of phosphorylation at S249 (P = 0.0221);Loss of phosphorylation at S249 (P = 0.0221);Loss of phosphorylation at S249 (P = 0.0221);Loss of phosphorylation at S249 (P = 0.0221);Loss of phosphorylation at S249 (P = 0.0221);
MVP		0.85
MPC		0.98
ClinPred		0.86	D
GERP RS		3.7
Varity_R		0.30
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs944092875; hg19: chr16-29825120; COSMIC: COSV54885190; COSMIC: COSV54885190;