rs76335820

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_145239.3(PRRT2):c.647C>A(p.Pro216His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,582,356 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts 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. P216R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00037 ( 3 hom. )

Consequence

PRRT2
NM_145239.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.28

Publications

25 publications found

Variant links:

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]

PRRT2 links:

ENSG00000280893 (HGNC:):

ENSG00000280893 links:

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

MVP-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010031402).

BP6

Variant 16-29813701-C-A is Benign according to our data. Variant chr16-29813701-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 206689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRT2	NM_145239.3 link	c.647C>A	p.Pro216His	missense_variant	Exon 2 of 4	ENST00000358758.12	NP_660282.2	Q7Z6L0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12 link	c.647C>A	p.Pro216His	missense_variant	Exon 2 of 4	1	NM_145239.3	ENSP00000351608.7		Q7Z6L0-1
ENSG00000280893	ENST00000609618.2 link	n.647C>A		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000476774.2		A0A0G2JLL6

Frequencies

GnomAD3 genomes

AF:

0.000382

AC:

AN:

151936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000506

AC:

110

AN:

217286

AF XY:

0.000558

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000653

Gnomad ASJ exome

AF:

0.00616

Gnomad EAS exome

AF:

0.000518

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000165

Gnomad OTH exome

AF:

0.000772

GnomAD4 exome

AF:

0.000368

AC:

526

AN:

1430300

Hom.:

Cov.:

AF XY:

0.000433

AC XY:

307

AN XY:

709434

show subpopulations

African (AFR)

AF:

0.0000310

AC:

AN:

32310

American (AMR)

AF:

0.0000489

AC:

AN:

40930

Ashkenazi Jewish (ASJ)

AF:

0.00825

AC:

198

AN:

24002

East Asian (EAS)

AF:

0.000230

AC:

AN:

39172

South Asian (SAS)

AF:

0.00131

AC:

107

AN:

81992

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51922

Middle Eastern (MID)

AF:

0.00107

AC:

AN:

5612

European-Non Finnish (NFE)

AF:

0.000154

AC:

169

AN:

1095536

Other (OTH)

AF:

0.000578

AC:

AN:

58824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.596

Heterozygous variant carriers

103

129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000381

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41500

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3468

East Asian (EAS)

AF:

0.00117

AC:

AN:

5142

South Asian (SAS)

AF:

0.00145

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

67950

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000772

Hom.:

Bravo

AF:

0.000287

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000372

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 01, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Episodic kinesigenic dyskinesia

Benign:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 28, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PRRT2-related disorder

Benign:1

Jul 02, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

not provided

Benign:1

Sep 29, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31124310, 26598494, 23363396, 26598493, 25502464, 23077024) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

T;.;.;.;.;T;.;T;T

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.70

.;.;T;T;T;.;T;.;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.010

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

0.90

L;L;L;.;L;L;.;L;L

PhyloP100

2.3

PrimateAI

Uncertain

0.56

PROVEAN

Benign

1.0

N;.;N;.;N;.;.;.;.

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

D;.;D;.;D;.;.;.;.

Sift4G

Uncertain

0.030

D;.;D;.;D;.;.;D;.

Polyphen

1.0

D;D;D;.;D;D;.;D;D

Vest4

0.30

MutPred

0.19

Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);

MVP

0.98

MPC

0.93

ClinPred

0.043

GERP RS

3.9

Varity_R

0.27

gMVP

0.32

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over