rs1555502548

Positions:

• chr16-29813062-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_145239.3(PRRT2):​c.8C>G​(p.Ala3Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000692 in 1,445,950 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: 0.0000069 (0 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.95

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13027933).
• BS2: High AC in GnomAdExome4 at 10 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.8C>G	p.Ala3Gly	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.8C>G	p.Ala3Gly	missense_variant	2/4	1	NM_145239.3	ENSP00000351608	P1
MVP-DT	ENST00000569039.5	n.246-2889G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000692 AC: 10 AN: 1445950 Hom.: 0 Cov.: 32 AF XY: 0.00000417 AC XY: 3 AN XY: 718726

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: 0.00000815

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 06, 2017

- -

Episodic kinesigenic dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2020

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: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PRRT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 448134). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glycine at codon 3 of the PRRT2 protein (p.Ala3Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.015	.;.;T;.;T;.;.;.;.;T;.;T;T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.75	T;T;.;.;T;T;T;T;T;.;T;.;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.5	.;.;L;L;.;L;.;.;L;L;.;L;L;.
MutationTaster	Benign	0.93	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.9	.;D;N;.;.;N;.;.;N;.;.;.;.;.
REVEL	Benign	0.095
Sift	Pathogenic	0.0	.;D;D;.;.;D;.;.;D;.;.;.;.;.
Sift4G	Benign	0.063	.;T;D;.;.;D;.;.;D;.;.;D;.;.
Polyphen		0.0010, 0.0030	.;.;B;B;.;B;.;.;B;B;.;B;B;.
Vest4		0.28, 0.28, 0.23
MutPred		0.16		Loss of stability (P = 0.0266);Loss of stability (P = 0.0266);Loss of stability (P = 0.0266);Loss of stability (P = 0.0266);Loss of stability (P = 0.0266);Loss of stability (P = 0.0266);Loss of stability (P = 0.0266);Loss of stability (P = 0.0266);Loss of stability (P = 0.0266);Loss of stability (P = 0.0266);Loss of stability (P = 0.0266);Loss of stability (P = 0.0266);Loss of stability (P = 0.0266);Loss of stability (P = 0.0266);
MVP		0.81
MPC		0.66
ClinPred		0.97	D
GERP RS		3.3
Varity_R		0.20
gMVP		0.064

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: rs1555502548; hg19: chr16-29824383;