NM_145239.3:c.916G>C

Variant names:

• chr16-29814369-G-C
• rs727504111
• NM_145239.3:c.916G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_145239.3(PRRT2):​c.916G>C​(p.Ala306Pro) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A306S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.01
• 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_145239.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-29814369-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 452494.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 16-29814369-G-C is Pathogenic according to our data. Variant chr16-29814369-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 536487.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRT2	NM_145239.3	c.916G>C	p.Ala306Pro	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.916G>C	p.Ala306Pro	missense_variant	Exon 3 of 4	1	NM_145239.3	ENSP00000351608.7
ENSG00000280893	ENST00000609618.2	n.905G>C		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

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Episodic kinesigenic dyskinesia Pathogenic:1

Jul 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 306 of the PRRT2 protein (p.Ala306Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with benign familial neonatal-infantile seizures (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 536487). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PRRT2 protein function with a positive predictive value of 95%. This variant disrupts the p.Ala306 amino acid residue in PRRT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23063574, 30392205, 31124310). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

not provided Uncertain:1

Mar 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31193310)

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;T;.;D;D;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.0	.;D;D;.;.;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.;H;H;H;H
PhyloP100		6.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.3	D;.;D;.;.;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0030	D;.;D;.;.;.
Sift4G	Pathogenic	0.0	D;.;D;.;D;.
Vest4		0.95
ClinPred		1.0	D
GERP RS		3.8
PromoterAI		-0.0051	Neutral
Varity_R		0.98
gMVP		1.0
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs727504111; hg19: chr16-29825690;