rs147268650

Positions:

• chr12-42472409-G-A
• chr12-42472409-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_153026.3(PRICKLE1):​c.108C>T​(p.Val36=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00455 in 1,614,088 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V36V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (23 hom.)
• Consequence: PRICKLE1 NM_153026.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.00

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 12-42472409-G-A is Benign according to our data. Variant chr12-42472409-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-42472409-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 23 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE1	NM_153026.3	c.108C>T	p.Val36=	synonymous_variant	2/8	ENST00000345127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.108C>T	p.Val36=	synonymous_variant	2/8	1	NM_153026.3	P1

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 564 AN: 152128 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.0571

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00597

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00329 AC: 827 AN: 251166 Hom.: 0 AF XY: 0.00331 AC XY: 450 AN XY: 135776

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00235

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00574

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00464 AC: 6781 AN: 1461842 Hom.: 23 Cov.: 31 AF XY: 0.00455 AC XY: 3311 AN XY: 727224

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00298

Gnomad4 FIN exome AF: 0.00120

Gnomad4 NFE exome AF: 0.00548

Gnomad4 OTH exome AF: 0.00430

GnomAD4 genome AF: 0.00370 AC: 564 AN: 152246 Hom.: 1 Cov.: 32 AF XY: 0.00339 AC XY: 252 AN XY: 74432

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00597

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00471 Hom.: 1

Bravo AF: 0.00361

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00627

EpiControl AF: 0.00498

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2013	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	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 13, 2016	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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

PRICKLE1: BP4, BP7 -

PRICKLE1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.17
DANN	Benign	0.62

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

Other links and lift over

dbSNP: rs147268650; hg19: chr12-42866211;