12-42459901-G-A

Position:

chr12-42459901-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_153026.3(PRICKLE1):c.2404C>T(p.Pro802Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,614,148 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P802P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

PRICKLE1
NM_153026.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 0.140

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002777487).

BP6

Variant 12-42459901-G-A is Benign according to our data. Variant chr12-42459901-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206656.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE1	NM_153026.3 linkuse as main transcript	c.2404C>T	p.Pro802Ser	missense_variant	8/8	ENST00000345127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE1	ENST00000345127.9 linkuse as main transcript	c.2404C>T	p.Pro802Ser	missense_variant	8/8	1	NM_153026.3	P1
	ENST00000547824.1 linkuse as main transcript	n.536G>A		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

223

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00442

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

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:

0.0000147

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000366

AC:

AN:

251460

Hom.:

AF XY:

0.000235

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00529

Gnomad AMR exome

AF:

0.000173

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:

0.000152

AC:

222

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00559

Gnomad4 AMR exome

AF:

0.000402

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.00146

AC:

223

AN:

152266

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00440

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000248

Hom.:

Bravo

AF:

0.00195

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000387

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2018	A variant of uncertain significance has been identified in the PRICKLE1 gene. The P802S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P802S variant is observed in 45/10,406 (0.4%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P802S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and Serine is observed at this position in another species. Additionally, 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 variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2017	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 02, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 26, 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. -

Epilepsy, progressive myoclonic, 1B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.6

DANN

Benign

0.62

DEOGEN2

Benign

0.029

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

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.74

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

M_CAP

Benign

0.0077

MetaRNN

Benign

0.0028

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

N;N;N;N;N;N;N;N;N;N

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

0.72

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

REVEL

Benign

0.087

Sift

Benign

0.40

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

Sift4G

Benign

0.42

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

Polyphen

0.0

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

Vest4

0.026

MVP

0.20

MPC

0.35

ClinPred

0.0026

GERP RS

-5.7

Varity_R

0.048

gMVP

0.18

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