16-29813066-C-A

Position:

• chr16-29813066-C-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS2_Supporting

The NM_145239.3(PRRT2):​c.12C>A​(p.Ser4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,448,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0890

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13736045).
• BS2: High AC in GnomAdExome4 at 5 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	UniProt
PRRT2	NM_145239.3	c.12C>A	p.Ser4Arg	missense_variant	2/4	ENST00000358758.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRRT2	ENST00000358758.12	c.12C>A	p.Ser4Arg	missense_variant	2/4	1	NM_145239.3	P1
MVP-DT	ENST00000569039.5	n.246-2893G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000418 AC: 1 AN: 239396 Hom.: 0 AF XY: 0.00000771 AC XY: 1 AN XY: 129752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000918

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1448428 Hom.: 0 Cov.: 32 AF XY: 0.00000555 AC XY: 4 AN XY: 720076

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: 0.00000452

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Oct 22, 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: "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 present in population databases (rs757148846, ExAC 0.002%). This sequence change replaces serine with arginine at codon 4 of the PRRT2 protein (p.Ser4Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	.;.;T;.;T;.;.;.;.;T;.;T;T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.74	T;T;.;.;T;T;T;T;T;.;T;.;T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.6	.;.;L;L;.;L;.;.;L;L;.;L;L;.
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.9	.;D;N;.;.;N;.;.;N;.;.;.;.;.
REVEL	Benign	0.13
Sift	Pathogenic	0.0	.;D;D;.;.;D;.;.;D;.;.;.;.;.
Sift4G	Uncertain	0.013	.;D;D;.;.;D;.;.;D;.;.;D;.;.
Polyphen		0.39, 0.74, 0.53	.;.;B;P;.;P;.;.;P;B;.;B;B;.
Vest4		0.36, 0.35, 0.32
MutPred		0.24		Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);Loss of phosphorylation at S4 (P = 0.0018);
MVP		0.82
MPC		0.87
ClinPred		0.98	D
GERP RS		2.2
Varity_R		0.25
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs757148846; hg19: chr16-29824387;