16-29813601-G-T

Variant names:

• chr16-29813601-G-T
• rs770599131
• NM_145239.3:c.547G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145239.3(PRRT2):​c.547G>T​(p.Ala183Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A183P) has been classified 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, single submitter U:1
• Conservation: PhyloP100: 2.52

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:):

MVP-DT (HGNC:56029): (MVP divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21517485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRT2	NM_145239.3	c.547G>T	p.Ala183Ser	missense_variant	Exon 2 of 4	ENST00000358758.12	NP_660282.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12	c.547G>T	p.Ala183Ser	missense_variant	Exon 2 of 4	1	NM_145239.3	ENSP00000351608.7
ENSG00000280893	ENST00000609618.2	n.547G>T		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000476774.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461200 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726856

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111698

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Episodic kinesigenic dyskinesia Uncertain:1

Jan 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 affected with PRRT2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 183 of the PRRT2 protein (p.Ala183Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;.;.;.;.;T;.;T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	.;.;T;T;T;.;T;.;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	L;L;L;.;L;L;.;L;L
PhyloP100		2.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.43	N;.;N;.;N;.;.;.;.
REVEL	Benign	0.11
Sift	Benign	0.037	D;.;D;.;D;.;.;.;.
Sift4G	Benign	0.33	T;.;T;.;T;.;.;T;.
Polyphen		0.70	P;P;P;.;P;P;.;P;P
Vest4		0.39
MutPred		0.14		Gain of phosphorylation at A183 (P = 0.0276);Gain of phosphorylation at A183 (P = 0.0276);Gain of phosphorylation at A183 (P = 0.0276);Gain of phosphorylation at A183 (P = 0.0276);Gain of phosphorylation at A183 (P = 0.0276);Gain of phosphorylation at A183 (P = 0.0276);Gain of phosphorylation at A183 (P = 0.0276);Gain of phosphorylation at A183 (P = 0.0276);Gain of phosphorylation at A183 (P = 0.0276);
MVP		0.80
MPC		0.62
ClinPred		0.74	D
GERP RS		4.0
Varity_R		0.096
gMVP		0.086

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs770599131; hg19: chr16-29824922;