rs758246761

chr16-29813773-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_145239.3(PRRT2):c.719G>A(p.Arg240Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000493 in 1,601,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.0230

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.123389035).
• BP6: Variant 16-29813773-G-A is Benign according to our data. Variant chr16-29813773-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241953.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRRT2	NM_145239.3	c.719G>A	p.Arg240Gln	missense_variant	2/4	ENST00000358758.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRRT2	ENST00000358758.12	c.719G>A	p.Arg240Gln	missense_variant	2/4	1	NM_145239.3	P1
MVP-DT	ENST00000569039.5	n.246-3600C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151966 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000209 AC: 5 AN: 238956 Hom.: 0 AF XY: 0.0000309 AC XY: 4 AN XY: 129362

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000302

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000697

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000511 AC: 74 AN: 1449340 Hom.: 0 Cov.: 43 AF XY: 0.0000569 AC XY: 41 AN XY: 720452

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000474

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000606

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151966 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74200

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2022

The c.719G>A (p.R240Q) alteration is located in exon 2 (coding exon 1) of the PRRT2 gene. This alteration results from a G to A substitution at nucleotide position 719, causing the arginine (R) at amino acid position 240 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Episodic kinesigenic dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.46
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.044	T;.;.;.;.;T;.;T;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.58	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.81	L;L;L;.;L;L;.;L;L
MutationTaster	Benign	0.68	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.2	N;.;N;.;N;.;.;.;.
REVEL	Benign	0.10
Sift	Uncertain	0.0040	D;.;D;.;D;.;.;.;.
Sift4G	Benign	0.10	T;.;T;.;T;.;.;T;.
Polyphen		0.90	P;D;P;.;D;P;.;P;P
Vest4		0.13
MutPred		0.15		Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);
MVP		0.86
MPC		0.93
ClinPred		0.50	D
GERP RS		3.9
Varity_R		0.23
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs758246761; hg19: chr16-29825094; COSMIC: COSV54885310; COSMIC: COSV54885310;