chr16-29813422-G-T

Position:

• chr16-29813422-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145239.3(PRRT2):​c.368G>T​(p.Gly123Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0510

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062259108).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRRT2	NM_145239.3	c.368G>T	p.Gly123Val	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.368G>T	p.Gly123Val	missense_variant	2/4	1	NM_145239.3	ENSP00000351608.7
ENSG00000280893	ENST00000609618.2	n.368G>T		non_coding_transcript_exon_variant	2/6	5		ENSP00000476774.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 15, 2019

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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"). This variant has not been reported in the literature in individuals with PRRT2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 123 of the PRRT2 protein (p.Gly123Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0077	.;T;.;.;.;.;T;.;T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.61	T;.;.;T;T;T;.;T;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.062	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.7	.;L;L;L;.;L;L;.;L;L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.52	.;N;.;N;.;N;.;.;.;.
REVEL	Benign	0.088
Sift	Uncertain	0.0030	.;D;.;D;.;D;.;.;.;.
Sift4G	Uncertain	0.015	.;D;.;D;.;D;.;.;D;.
Polyphen		0.0020, 0.98, 0.010	.;B;D;B;.;D;B;.;B;B
Vest4		0.26, 0.29, 0.21, 0.26
MutPred		0.10		Loss of catalytic residue at G123 (P = 0.1231);Loss of catalytic residue at G123 (P = 0.1231);Loss of catalytic residue at G123 (P = 0.1231);Loss of catalytic residue at G123 (P = 0.1231);Loss of catalytic residue at G123 (P = 0.1231);Loss of catalytic residue at G123 (P = 0.1231);Loss of catalytic residue at G123 (P = 0.1231);Loss of catalytic residue at G123 (P = 0.1231);Loss of catalytic residue at G123 (P = 0.1231);Loss of catalytic residue at G123 (P = 0.1231);
MVP		0.45
MPC		0.96
ClinPred		0.24	T
GERP RS		1.3
Varity_R		0.035
gMVP		0.062

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: rs758798693; hg19: chr16-29824743;