chr16-29814403-G-A

Variant names:

• chr16-29814403-G-A
• rs387907125
• NM_145239.3:c.950G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.53
• Publications: 9 publications found

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]

ENSG00000280893 (HGNC:):

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

ACMG classification

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	c.950G>A	p.Ser317Asn	missense_variant	Exon 3 of 4	ENST00000358758.12	NP_660282.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12	c.950G>A	p.Ser317Asn	missense_variant	Exon 3 of 4	1	NM_145239.3	ENSP00000351608.7
ENSG00000280893	ENST00000609618.2	n.939G>A		non_coding_transcript_exon_variant	Exon 3 of 6	5		ENSP00000476774.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	29
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	D
LIST_S2	Uncertain	0.89	.;D;T;.;.;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	0.96	L;.;L;L;L;L
PhyloP100		4.5
PrimateAI	Uncertain	0.72	T
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	D
GERP RS		3.8
PromoterAI		0.063	Neutral
Varity_R		0.82
gMVP		0.99
Mutation Taster		=30/70	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387907125; hg19: chr16-29825724;