rs144843013

Positions:

• chr12-42470315-G-A

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.177C>T​(p.Tyr59Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,613,942 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (33 hom.)
• Consequence: PRICKLE1 NM_153026.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.151

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 12-42470315-G-A is Benign according to our data. Variant chr12-42470315-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.151 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRICKLE1	NM_153026.3	c.177C>T	p.Tyr59Tyr	synonymous_variant	3/8	ENST00000345127.9	NP_694571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.177C>T	p.Tyr59Tyr	synonymous_variant	3/8	1	NM_153026.3	ENSP00000345064.3

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 293 AN: 152118 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00353 AC: 887 AN: 251274 Hom.: 12 AF XY: 0.00433 AC XY: 588 AN XY: 135828

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0148

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00235

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00282 AC: 4126 AN: 1461706 Hom.: 33 Cov.: 30 AF XY: 0.00328 AC XY: 2387 AN XY: 727170

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00349

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0156

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.00214

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.00193 AC: 294 AN: 152236 Hom.: 2 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74446

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0153

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00234

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00221 Hom.: 0

Bravo AF: 0.00161

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00409

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	May 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 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)	Dec 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 14, 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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PRICKLE1: BP4, BP7, BS1, BS2 -

Epilepsy, progressive myoclonic, 1B Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.0
DANN	Benign	0.85

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: rs144843013; hg19: chr12-42864117; COSMIC: COSV61544397; COSMIC: COSV61544397;