chr12-42469464-C-T

Position:

chr12-42469464-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000345127.9(PRICKLE1):c.370G>A(p.Ala124Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00676 in 1,614,184 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A124A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0071 ( 44 hom., cov: 32)

Exomes 𝑓: 0.0067 ( 226 hom. )

Consequence

PRICKLE1
ENST00000345127.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:7

Conservation

PhyloP100: 1.95

Variant links:

Genes affected

PRICKLE1 (HGNC:17019): (prickle planar cell polarity protein 1) This gene encodes a nuclear receptor that may be a negative regulator of the Wnt/beta-catenin signaling pathway. The encoded protein localizes to the nuclear membrane and has been implicated in the nuclear trafficking of the transcription repressors REST/NRSF and REST4. Mutations in this gene have been linked to progressive myoclonus epilepsy. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 3. [provided by RefSeq, Sep 2009]

PRICKLE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001621902).

BP6

Variant 12-42469464-C-T is Benign according to our data. Variant chr12-42469464-C-T is described in ClinVar as [Benign]. Clinvar id is 130027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-42469464-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRICKLE1	NM_153026.3 linkuse as main transcript	c.370G>A	p.Ala124Thr	missense_variant	4/8	ENST00000345127.9	NP_694571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRICKLE1	ENST00000345127.9 linkuse as main transcript	c.370G>A	p.Ala124Thr	missense_variant	4/8	1	NM_153026.3	ENSP00000345064	P1

Frequencies

GnomAD3 genomes

AF:

0.00709

AC:

1080

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0118

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.0920

Gnomad SAS

AF:

0.0370

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00267

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.0141

AC:

3542

AN:

251392

Hom.:

AF XY:

0.0140

AC XY:

1900

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.0168

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.0955

Gnomad SAS exome

AF:

0.0271

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00254

Gnomad OTH exome

AF:

0.00717

GnomAD4 exome

AF:

0.00673

AC:

9839

AN:

1461840

Hom.:

226

Cov.:

AF XY:

0.00734

AC XY:

5341

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.0158

Gnomad4 ASJ exome

AF:

0.00214

Gnomad4 EAS exome

AF:

0.0834

Gnomad4 SAS exome

AF:

0.0265

Gnomad4 FIN exome

AF:

0.000318

Gnomad4 NFE exome

AF:

0.00255

Gnomad4 OTH exome

AF:

0.00970

GnomAD4 genome

AF:

0.00708

AC:

1079

AN:

152344

Hom.:

Cov.:

AF XY:

0.00819

AC XY:

610

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000745

Gnomad4 AMR

AF:

0.0122

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.0910

Gnomad4 SAS

AF:

0.0373

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00268

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00711

Hom.:

Bravo

AF:

0.00841

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.0135

AC:

1644

Asia WGS

AF:

0.0530

AC:

185

AN:

3478

EpiCase

AF:

0.00327

EpiControl

AF:

0.00302

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 02, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 22, 2016	This alteration is classified as 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. -

Childhood epilepsy with centrotemporal spikes

Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Epilepsy, progressive myoclonic, 1B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;T;T;T;T;T;T;T;T;T;T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

0.0089

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.82

.;.;.;.;.;.;.;.;.;T;T;T

MetaRNN

Benign

0.0016

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.84

L;L;L;L;L;L;L;L;L;L;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.2

N;.;N;.;N;.;.;N;.;N;N;.

REVEL

Benign

0.099

Sift

Benign

0.18

T;.;T;.;T;.;.;T;.;T;T;.

Sift4G

Benign

0.26

T;.;T;.;T;.;.;T;.;T;.;.

Polyphen

0.0020

B;B;B;B;B;B;B;B;B;B;.;.

Vest4

0.078

MPC

0.34

ClinPred

0.0076

GERP RS

3.5

Varity_R

0.087

gMVP

0.31

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

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