16-29813703-C-G

Position:

• chr16-29813703-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.22

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 Uncertain_significance. Variant got 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/exons	MANE	Protein	UniProt
PRRT2	NM_145239.3	c.649C>G	p.Arg217Gly	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.649C>G	p.Arg217Gly	missense_variant	2/4	1	NM_145239.3	ENSP00000351608.7
ENSG00000280893	ENST00000609618.2	n.649C>G		non_coding_transcript_exon_variant	2/6	5		ENSP00000476774.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1426562 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 707416

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: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

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

Mar 03, 2021

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 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: "Probably 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 arginine with glycine at codon 217 of the PRRT2 protein (p.Arg217Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2021

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	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
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	N
LIST_S2	Benign	0.80	.;.;T;T;T;.;T;.;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.81	L;L;L;.;L;L;.;L;L
PrimateAI	Uncertain	0.52	T
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	D
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

LitVar

Other links and lift over

dbSNP: rs77838305; hg19: chr16-29825024;