16-29814369-G-T

Position:

• chr16-29814369-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_145239.3(PRRT2):​c.916G>T​(p.Ala306Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.01

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 16-29814369-G-T is Pathogenic according to our data. Variant chr16-29814369-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 452494.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRRT2	NM_145239.3	c.916G>T	p.Ala306Ser	missense_variant	3/4	ENST00000358758.12	NP_660282.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12	c.916G>T	p.Ala306Ser	missense_variant	3/4	1	NM_145239.3	ENSP00000351608	P1
MVP-DT	ENST00000569039.5	n.246-4196C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457098 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 724958

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 23, 2023

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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 452494). This variant has not been reported in the literature in individuals affected with PRRT2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 306 of the PRRT2 protein (p.Ala306Ser). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 09, 2017

The A306S variant in the PRRT2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, different missense variants in the same residue (A306T, A306D) have been reported previously in association with PRRT2-related disorders (Marini et al., 2012; Cai et al., 2013). The A306S variant is not observed in large population cohorts (Lek et al., 2016). The A306S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret A306S as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;T;.;D;D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	.;D;D;.;.;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.0	N;.;N;.;.;.
REVEL	Pathogenic	0.90
Sift	Benign	0.054	T;.;D;.;.;.
Sift4G	Pathogenic	0.0	D;.;D;.;D;.
Polyphen		1.0	D;.;D;D;D;D
Vest4		0.75
MutPred		0.74		Gain of disorder (P = 0.0257);.;Gain of disorder (P = 0.0257);Gain of disorder (P = 0.0257);Gain of disorder (P = 0.0257);Gain of disorder (P = 0.0257);
MVP		1.0
MPC		0.83
ClinPred		0.95	D
GERP RS		3.8
Varity_R		0.51
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504111; hg19: chr16-29825690;