16-29813068-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_145239.3(PRRT2):c.14G>C(p.Ser5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,453,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S5S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.369

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.052841842).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRRT2	NM_145239.3	c.14G>C	p.Ser5Thr	missense_variant	2/4	ENST00000358758.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRRT2	ENST00000358758.12	c.14G>C	p.Ser5Thr	missense_variant	2/4	1	NM_145239.3	P1
MVP-DT	ENST00000569039.5	n.246-2895C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000123 AC: 3 AN: 243874 Hom.: 0 AF XY: 0.00000757 AC XY: 1 AN XY: 132026

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000605

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: 0.00000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000213 AC: 31 AN: 1453658 Hom.: 0 Cov.: 32 AF XY: 0.0000249 AC XY: 18 AN XY: 723024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000464

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: 0.0000262

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000285 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

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

Sep 14, 2023

This variant is present in population databases (rs745742339, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 5 of the PRRT2 protein (p.Ser5Thr). 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: 206682). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	13
Dann	Benign	0.89
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.63	T;T;.;.;T;T;T;T;T;.;T;.;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.053	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.34	T
Polyphen		0.0030, 0.0090, 0.0050	.;.;B;B;.;B;.;.;B;B;.;B;B;.
Vest4		0.12, 0.11, 0.10, 0.12
MutPred		0.13		Loss of phosphorylation at I5 (P = 0.0665);Loss of phosphorylation at I5 (P = 0.0665);Loss of phosphorylation at I5 (P = 0.0665);Loss of phosphorylation at I5 (P = 0.0665);Loss of phosphorylation at I5 (P = 0.0665);Loss of phosphorylation at I5 (P = 0.0665);Loss of phosphorylation at I5 (P = 0.0665);Loss of phosphorylation at I5 (P = 0.0665);Loss of phosphorylation at I5 (P = 0.0665);Loss of phosphorylation at I5 (P = 0.0665);Loss of phosphorylation at I5 (P = 0.0665);Loss of phosphorylation at I5 (P = 0.0665);Loss of phosphorylation at I5 (P = 0.0665);Loss of phosphorylation at I5 (P = 0.0665);
MVP		0.67
MPC		0.23
ClinPred		0.026	T
GERP RS		0.95
Varity_R		0.12
gMVP		0.062

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: rs745742339; hg19: chr16-29824389;