rs3827522

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_153026.3(PRICKLE1):c.2236C>T(p.Pro746Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00543 in 1,614,082 control chromosomes in the GnomAD database, including 192 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 34 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 158 hom. )

Consequence

PRICKLE1
NM_153026.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 7.55

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

epilepsy, progressive myoclonic, 1B
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Unverricht-Lundborg syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
progressive myoclonus epilepsy
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PRICKLE1 links:

ENSG00000257225 (HGNC:58444):

ENSG00000257225 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017695427).

BP6

Variant 12-42460069-G-A is Benign according to our data. Variant chr12-42460069-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRICKLE1	NM_153026.3 link	c.2236C>T	p.Pro746Ser	missense_variant	Exon 8 of 8	ENST00000345127.9	NP_694571.2	Q96MT3A0A024R0W7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRICKLE1	ENST00000345127.9 link	c.2236C>T	p.Pro746Ser	missense_variant	Exon 8 of 8	1	NM_153026.3	ENSP00000345064.3		Q96MT3

Frequencies

GnomAD3 genomes

AF:

0.00600

AC:

913

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.0856

Gnomad SAS

AF:

0.0104

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00266

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.0110

AC:

2770

AN:

251268

AF XY:

0.0101

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.0168

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.0888

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00254

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00537

AC:

7856

AN:

1461880

Hom.:

158

Cov.:

AF XY:

0.00545

AC XY:

3966

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.0158

AC:

706

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00214

AC:

AN:

26136

East Asian (EAS)

AF:

0.0795

AC:

3156

AN:

39700

South Asian (SAS)

AF:

0.00714

AC:

616

AN:

86258

European-Finnish (FIN)

AF:

0.000318

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00253

AC:

2811

AN:

1112012

Other (OTH)

AF:

0.00760

AC:

459

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

543

1086

1628

2171

2714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

166

332

498

664

830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00600

AC:

913

AN:

152202

Hom.:

Cov.:

AF XY:

0.00652

AC XY:

485

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41536

American (AMR)

AF:

0.0121

AC:

185

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3466

East Asian (EAS)

AF:

0.0847

AC:

438

AN:

5174

South Asian (SAS)

AF:

0.0108

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00266

AC:

181

AN:

68008

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00538

Hom.:

Bravo

AF:

0.00795

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.0101

AC:

1231

Asia WGS

AF:

0.0350

AC:

122

AN:

3478

EpiCase

AF:

0.00327

EpiControl

AF:

0.00302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 14, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Jul 02, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 22, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Epilepsy, progressive myoclonic, 1B

Benign:2

Oct 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

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

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.057

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.75

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

MetaRNN

Benign

0.0018

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

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.7

L;L;L;L;L;L;L;L;L;L

PhyloP100

7.5

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.5

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

REVEL

Uncertain

0.30

Sift

Uncertain

0.018

D;.;D;.;D;.;.;D;.;D

Sift4G

Benign

0.16

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

Polyphen

0.037

B;B;B;B;B;B;B;B;B;B

Vest4

0.10

MPC

0.39

ClinPred

0.061

GERP RS

5.6

Varity_R

0.086

gMVP

0.36

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over