rs200926711

chr16-29813698-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_145239.3(PRRT2):c.644C>G(p.Pro215Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000393 in 1,575,196 control chromosomes in the GnomAD database, including 6 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P215S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00046 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (5 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.721

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004953712).
• BP6: Variant 16-29813698-C-G is Benign according to our data. Variant chr16-29813698-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 206688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-29813698-C-G is described in Lovd as [Benign]. Variant chr16-29813698-C-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 71 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRRT2	NM_145239.3	c.644C>G	p.Pro215Arg	missense_variant	2/4	ENST00000358758.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRRT2	ENST00000358758.12	c.644C>G	p.Pro215Arg	missense_variant	2/4	1	NM_145239.3	P1
MVP-DT	ENST00000569039.5	n.246-3525G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000468 AC: 71 AN: 151636 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00230

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00272

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000844 AC: 183 AN: 216884 Hom.: 2 AF XY: 0.00107 AC XY: 126 AN XY: 118062

Gnomad AFR exome AF: 0.0000723

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00577

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00289

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.000774

GnomAD4 exome AF: 0.000386 AC: 549 AN: 1423432 Hom.: 5 Cov.: 36 AF XY: 0.000510 AC XY: 360 AN XY: 706426

Gnomad4 AFR exome AF: 0.0000311

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00500

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00230

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000115

Gnomad4 OTH exome AF: 0.000700

GnomAD4 genome AF: 0.000461 AC: 70 AN: 151764 Hom.: 1 Cov.: 31 AF XY: 0.000553 AC XY: 41 AN XY: 74192

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00251

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000811 Hom.: 1

Bravo AF: 0.000706

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000471 AC: 4

ExAC AF: 0.000769 AC: 93

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2019	This variant is associated with the following publications: (PMID: 23077024, 22243967, 23566103, 31124310, 24594579) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	PRRT2: BS2 -

Episodic kinesigenic dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Seizures, benign familial infantile, 2;C1865926:Infantile convulsions and choreoathetosis;C4552000:Episodic kinesigenic dyskinesia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 12, 2021

- -

PRRT2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;.;.;.;T;.;T;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0050	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.90	L;L;L;.;L;L;.;L;L
MutationTaster	Benign	0.58	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.11	N;.;N;.;N;.;.;.;.
REVEL	Benign	0.22
Sift	Uncertain	0.0080	D;.;D;.;D;.;.;.;.
Sift4G	Uncertain	0.048	D;.;D;.;D;.;.;D;.
Polyphen		1.0	D;D;D;.;D;D;.;D;D
Vest4		0.27
MVP		0.94
MPC		0.90
ClinPred		0.022	T
GERP RS		2.9
Varity_R		0.075
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs200926711; hg19: chr16-29825019;