rs3827522

chr12-42460069-G-Achr12-42460069-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 12/20 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.55

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 130026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-42460069-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
PRICKLE1	NM_153026.3	c.2236C>T	p.Pro746Ser	missense_variant	8/8	ENST00000345127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.2236C>T	p.Pro746Ser	missense_variant	8/8	1	NM_153026.3	P1
	ENST00000547824.1	n.704G>A		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 913 AN: 152084 Hom.: 32 Cov.: 32

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

GnomAD3 exomes AF: 0.0110 AC: 2770 AN: 251268 Hom.: 78 AF XY: 0.0101 AC XY: 1367 AN XY: 135804

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 SAS exome AF: 0.00627

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.: 34 AF XY: 0.00545 AC XY: 3966 AN XY: 727238

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.0158

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.0795

Gnomad4 SAS exome AF: 0.00714

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00253

Gnomad4 OTH exome AF: 0.00760

GnomAD4 genome AF: 0.00600 AC: 913 AN: 152202 Hom.: 34 Cov.: 32 AF XY: 0.00652 AC XY: 485 AN XY: 74412

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0847

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00598 Hom.: 63

Bravo AF: 0.00795

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00221 AC: 19

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2012	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)	Jul 02, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 22, 2016	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -

Epilepsy, progressive myoclonic, 1B Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 14, 2021	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

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

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	23
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	D
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	L;L;L;L;L;L;L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.34	T
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	T
GERP RS		5.6
Varity_R		0.086
gMVP		0.36

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: rs3827522; hg19: chr12-42853871; COSMIC: COSV100453522; COSMIC: COSV100453522;