rs139747674

Positions:

chr3-64157305-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_198859.4(PRICKLE2):c.457G>A(p.Val153Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,614,084 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 0.0012 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

PRICKLE2
NM_198859.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.19

Variant links:

Genes affected

PRICKLE2 (HGNC:20340): (prickle planar cell polarity protein 2) This gene encodes a homolog of Drosophila prickle. The exact function of this gene is not known, however, studies in mice suggest that it may be involved in seizure prevention. Mutations in this gene are associated with progressive myoclonic epilepsy type 5. [provided by RefSeq, Dec 2011]

PRICKLE2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009881824).

BP6

Variant 3-64157305-C-T is Benign according to our data. Variant chr3-64157305-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242689.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=3}. Variant chr3-64157305-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00119 (181/152336) while in subpopulation EAS AF= 0.00116 (6/5186). AF 95% confidence interval is 0.000795. There are 1 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 181 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE2	NM_198859.4 linkuse as main transcript	c.457G>A	p.Val153Ile	missense_variant	5/8	ENST00000638394.2
PRICKLE2	NM_001370528.1 linkuse as main transcript	c.457G>A	p.Val153Ile	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PRICKLE2	ENST00000638394.2 linkuse as main transcript	c.457G>A	p.Val153Ile	missense_variant	5/8	1	NM_198859.4
PRICKLE2	ENST00000295902.11 linkuse as main transcript	c.625G>A	p.Val209Ile	missense_variant	6/9	5		P1
PRICKLE2	ENST00000564377.6 linkuse as main transcript	c.457G>A	p.Val153Ile	missense_variant	5/8	5
PRICKLE2	ENST00000640303.1 linkuse as main transcript	n.1096G>A		non_coding_transcript_exon_variant	3/6	5

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

181

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00696

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00131

AC:

328

AN:

250304

Hom.:

AF XY:

0.00117

AC XY:

158

AN XY:

135486

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00239

Gnomad EAS exome

AF:

0.00120

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00694

Gnomad NFE exome

AF:

0.000913

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.00108

AC:

1576

AN:

1461748

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

742

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00287

Gnomad4 EAS exome

AF:

0.000479

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.00562

Gnomad4 NFE exome

AF:

0.000926

Gnomad4 OTH exome

AF:

0.00167

GnomAD4 genome

AF:

0.00119

AC:

181

AN:

152336

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00696

Gnomad4 NFE

AF:

0.000985

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.000831

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00107

AC:

130

EpiCase

AF:

0.000709

EpiControl

AF:

0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Progressive myoclonic epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 10, 2015

- -

Myoclonic epilepsy, progressive, X-linked

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 06, 2018

- -

Progressive myoclonic epilepsy type 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.76

.;T;T

M_CAP

Benign

0.043

MetaRNN

Benign

0.0099

T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.6

L;L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.33

REVEL

Benign

0.21

Polyphen

0.0030

B;B;.

MVP

0.28

MPC

0.39

ClinPred

0.017

GERP RS

3.9

Varity_R

0.069

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over