rs566073131

Positions:

chr12-42472492-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_153026.3(PRICKLE1):c.25A>G(p.Met9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M9I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PRICKLE1
NM_153026.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.04

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 Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018887639).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE1	NM_153026.3 linkuse as main transcript	c.25A>G	p.Met9Val	missense_variant	2/8	ENST00000345127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE1	ENST00000345127.9 linkuse as main transcript	c.25A>G	p.Met9Val	missense_variant	2/8	1	NM_153026.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251400

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000118

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2022

The c.25A>G (p.M9V) alteration is located in exon 2 (coding exon 1) of the PRICKLE1 gene. This alteration results from a A to G substitution at nucleotide position 25, causing the methionine (M) at amino acid position 9 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Epilepsy, progressive myoclonic, 1B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 15, 2022

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 9 of the PRICKLE1 protein (p.Met9Val). This variant is present in population databases (rs566073131, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with PRICKLE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 206657). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2017

p.Met9Val (ATG>GTG): c.25 A>G in exon 2 of the PRICKLE1 gene (NM_153026.2). The c.25 A>G variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Multiple in silico algorithms predict c.25 A>G may create a cryptic splice donor site upstream of the natural donor site. However, in the absence of RNA/functional studies, the actual effect of the c.25 A>G on splicing is unknown. If c.25 A>G does not alter splicing, it will result in the M9V missense change which is a conservative amino acid substitution that is not likely to impact secondary protein structure as these residues share similar properties. In addition, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.031

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

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.81

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

M_CAP

Benign

0.015

MetaRNN

Benign

0.019

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

MetaSVM

Benign

-0.88

MutationAssessor

Benign

-0.060

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

MutationTaster

Benign

0.99

N;N;N;N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.30

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

REVEL

Benign

0.091

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0

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

Vest4

0.16

MutPred

0.12

Loss of glycosylation at P7 (P = 0.0732);Loss of glycosylation at P7 (P = 0.0732);Loss of glycosylation at P7 (P = 0.0732);Loss of glycosylation at P7 (P = 0.0732);Loss of glycosylation at P7 (P = 0.0732);Loss of glycosylation at P7 (P = 0.0732);Loss of glycosylation at P7 (P = 0.0732);Loss of glycosylation at P7 (P = 0.0732);Loss of glycosylation at P7 (P = 0.0732);Loss of glycosylation at P7 (P = 0.0732);Loss of glycosylation at P7 (P = 0.0732);Loss of glycosylation at P7 (P = 0.0732);Loss of glycosylation at P7 (P = 0.0732);Loss of glycosylation at P7 (P = 0.0732);Loss of glycosylation at P7 (P = 0.0732);

MVP

0.45

MPC

0.35

ClinPred

0.027

GERP RS

5.4

Varity_R

0.095

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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