Genetic Variant NM_145239.3:c.950G>A (chr16-29814403-G-A) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3PP5_Moderate

The NM_145239.3(PRRT2):c.950G>A(p.Ser317Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S317R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

PRRT2
NM_145239.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.53

Publications

9 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_145239.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

PP5

Variant 16-29814403-G-A is Pathogenic according to our data. Variant chr16-29814403-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 31172.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRT2	NM_145239.3 link	c.950G>A	p.Ser317Asn	missense_variant	Exon 3 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.950G>A	p.Ser317Asn	missense_variant	Exon 3 of 4	1	NM_145239.3	ENSP00000351608.7		Q7Z6L0-1
ENSG00000280893	ENST00000609618.2 link	n.939G>A		non_coding_transcript_exon_variant	Exon 3 of 6	5		ENSP00000476774.2		A0A0G2JLL6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Episodic kinesigenic dyskinesia

Pathogenic:1

Dec 08, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects PRRT2 protein function (PMID: 31124310). This sequence change replaces serine with asparagine at codon 317 of the PRRT2 protein (p.Ser317Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with infantile convulsions and choreoathetosis syndrome (PMID: 22243967). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31172). -

Infantile convulsions and choreoathetosis

Pathogenic:1

Jan 13, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.42

T;T;.;T;T;T

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.89

.;D;T;.;.;T

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

0.96

L;.;L;L;L;L

PhyloP100

4.5

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.9

D;.;D;.;.;.

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

D;.;D;.;.;.

Sift4G

Uncertain

0.0060

D;.;D;.;D;.

Polyphen

1.0

D;.;D;D;D;D

Vest4

0.97

MutPred

0.62

Loss of ubiquitination at K314 (P = 0.1062);.;Loss of ubiquitination at K314 (P = 0.1062);Loss of ubiquitination at K314 (P = 0.1062);Loss of ubiquitination at K314 (P = 0.1062);Loss of ubiquitination at K314 (P = 0.1062);

MVP

0.99

MPC

0.84

ClinPred

0.97

GERP RS

3.8

PromoterAI

0.063

Neutral

(source)

Varity_R

0.82

gMVP

0.99

Mutation Taster

=30/70

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over