rs745594874

Positions:

• chr16-29813694-G-C
• chr16-29813694-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5 BP4_Strong BP6 BS2

The NM_145239.3(PRRT2):​c.640G>C​(p.Ala214Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000802 in 1,355,752 control chromosomes in the GnomAD database, including 1 homozygotes. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A214G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00091 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00080 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.749

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.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-29813694-G-CC is described in ClinVar as [Pathogenic]. Clinvar id is 2504178.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008581936).
• BP6: Variant 16-29813694-G-C is Benign according to our data. Variant chr16-29813694-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206687.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=4}. Variant chr16-29813694-G-C is described in Lovd as [Benign].
• BS2: High AC in GnomAdExome4 at 1087 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRRT2	NM_145239.3	c.640G>C	p.Ala214Pro	missense_variant	2/4	ENST00000358758.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRRT2	ENST00000358758.12	c.640G>C	p.Ala214Pro	missense_variant	2/4	1	NM_145239.3	P1
MVP-DT	ENST00000569039.5	n.246-3521C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 137 AN: 149504 Hom.: 2 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000266

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.00234

Gnomad SAS AF: 0.00276

Gnomad FIN AF: 0.0000969

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.000581

Gnomad OTH AF: 0.000971

GnomAD3 exomes AF: 0.00152 AC: 206 AN: 135540 Hom.: 0 AF XY: 0.00165 AC XY: 121 AN XY: 73520

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.000680

Gnomad EAS exome AF: 0.00527

Gnomad SAS exome AF: 0.00391

Gnomad FIN exome AF: 0.0000660

Gnomad NFE exome AF: 0.000910

Gnomad OTH exome AF: 0.000623

GnomAD4 exome AF: 0.000802 AC: 1087 AN: 1355752 Hom.: 1 Cov.: 36 AF XY: 0.000836 AC XY: 562 AN XY: 672552

Gnomad4 AFR exome AF: 0.000787

Gnomad4 AMR exome AF: 0.000473

Gnomad4 ASJ exome AF: 0.000438

Gnomad4 EAS exome AF: 0.00378

Gnomad4 SAS exome AF: 0.00323

Gnomad4 FIN exome AF: 0.0000798

Gnomad4 NFE exome AF: 0.000559

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000909 AC: 136 AN: 149604 Hom.: 2 Cov.: 31 AF XY: 0.000876 AC XY: 64 AN XY: 73022

Gnomad4 AFR AF: 0.00155

Gnomad4 AMR AF: 0.000266

Gnomad4 ASJ AF: 0.000291

Gnomad4 EAS AF: 0.00235

Gnomad4 SAS AF: 0.00255

Gnomad4 FIN AF: 0.0000969

Gnomad4 NFE AF: 0.000582

Gnomad4 OTH AF: 0.000962

Alfa AF: 0.000472 Hom.: 0

ExAC AF: 0.00102 AC: 123

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2020	This variant is associated with the following publications: (PMID: 23496026, 27123484, 22101681, 26598493, 24594579, 27907910, 31124310) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PRRT2: BP4, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 19, 2021

- -

Episodic kinesigenic dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

PRRT2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 19, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0052	T;.;.;.;.;T;.;T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0086	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.90	L;L;L;.;L;L;.;L;L
MutationTaster	Benign	0.78	N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.82	N;.;N;.;N;.;.;.;.
REVEL	Benign	0.21
Sift	Uncertain	0.022	D;.;D;.;D;.;.;.;.
Sift4G	Benign	0.12	T;.;T;.;T;.;.;T;.
Polyphen		1.0	D;D;D;.;D;D;.;D;D
Vest4		0.58
MVP		0.87
MPC		1.0
ClinPred		0.023	T
GERP RS		3.9
Varity_R		0.20
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs745594874; hg19: chr16-29825015; COSMIC: COSV54881935; COSMIC: COSV54881935;