16-29813701-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_145239.3(PRRT2):c.647C>G(p.Pro216Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,582,238 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P216H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

PRRT2
NM_145239.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4O:1

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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23823166).

BP6

Variant 16-29813701-C-G is Benign according to our data. Variant chr16-29813701-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 65757.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRT2	NM_145239.3 link	c.647C>G	p.Pro216Arg	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>G	p.Pro216Arg	missense_variant	Exon 2 of 4	1	NM_145239.3	ENSP00000351608.7		Q7Z6L0-1
ENSG00000280893	ENST00000609618.2 link	n.647C>G		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000476774.2		A0A0G2JLL6

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

151936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000152

AC:

AN:

217286

AF XY:

0.000144

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000576

Gnomad FIN exome

AF:

0.000101

Gnomad NFE exome

AF:

0.000165

Gnomad OTH exome

AF:

0.000386

GnomAD4 exome

AF:

0.000159

AC:

228

AN:

1430302

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

112

AN XY:

709432

show subpopulations

African (AFR)

AF:

0.0000619

AC:

AN:

32310

American (AMR)

AF:

0.000293

AC:

AN:

40928

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24004

East Asian (EAS)

AF:

0.0000511

AC:

AN:

39174

South Asian (SAS)

AF:

0.000146

AC:

AN:

81992

European-Finnish (FIN)

AF:

0.0000578

AC:

AN:

51922

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5612

European-Non Finnish (NFE)

AF:

0.000173

AC:

189

AN:

1095536

Other (OTH)

AF:

0.000119

AC:

AN:

58824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.602

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000987

AC:

AN:

151936

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74198

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41378

American (AMR)

AF:

0.0000655

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67958

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

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:

0.0000123

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.0000992

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Episodic kinesigenic dyskinesia 1

Benign:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Nov 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PRRT2 c.647C>G (p.Pro216Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 217286 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PRRT2 causing Episodic Kinesigenic Dyskinesia 1, allowing no conclusion about variant significance. c.647C>G has been reported in the literature in individuals affected with Episodic Kinesigenic Dyskinesia, without strong evidence for causality (Liu _2013). These report(s) do not provide unequivocal conclusions about association of the variant with Episodic Kinesigenic Dyskinesia 1. Co-occurrences with other pathogenic variant(s) have been reported (PRRT2 c.510dup, p.Leu171SerfsX3), providing supporting evidence for a benign role (Liu _2013). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Zhao_2019). ClinVar contains an entry for this variant (Variation ID: 65757). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Infantile convulsions and choreoathetosis

Uncertain:1

Mar 01, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Episodic kinesigenic dyskinesia

Benign:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Feb 29, 2024

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. -

not provided

Benign:1

Mar 27, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20301633, 25502464, 23190448, 26598493, 31124310, 31154286) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

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

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.76

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

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.24

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

MetaSVM

Uncertain

0.45

MutationAssessor

Benign

0.90

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

PhyloP100

2.3

PrimateAI

Uncertain

0.58

PROVEAN

Benign

0.47

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

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

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

Sift4G

Benign

0.10

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

Polyphen

0.99

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

Vest4

0.33

MVP

0.98

MPC

0.89

ClinPred

0.12

GERP RS

3.9

Varity_R

0.26

gMVP

0.34

Mutation Taster

=13/87

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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