rs763169354

Positions:

• chr12-42464413-C-A
• chr12-42464413-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_153026.3(PRICKLE1):​c.1621G>T​(p.Ala541Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85

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]

ENSG00000257225 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28370535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRICKLE1	NM_153026.3	c.1621G>T	p.Ala541Ser	missense_variant	7/8	ENST00000345127.9	NP_694571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.1621G>T	p.Ala541Ser	missense_variant	7/8	1	NM_153026.3	ENSP00000345064.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251446 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000756

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 Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, progressive myoclonic, 1B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2021

This sequence change replaces alanine with serine at codon 541 of the PRICKLE1 protein (p.Ala541Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs763169354, ExAC 0.02%). This missense change has been observed in individual(s) with epilepsy (PMID: 31875159). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;T;T;T;T;T;T;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;.;.;.;.;.;.;.;.;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.2	M;M;M;M;M;M;M;M;M;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.77	N;.;N;.;N;.;.;N;.;N
REVEL	Benign	0.17
Sift	Uncertain	0.027	D;.;D;.;D;.;.;D;.;D
Sift4G	Benign	0.30	T;.;T;.;T;.;.;T;.;T
Polyphen		0.93	P;P;P;P;P;P;P;P;P;P
Vest4		0.53
MutPred		0.14		Gain of phosphorylation at A541 (P = 0.0337);Gain of phosphorylation at A541 (P = 0.0337);Gain of phosphorylation at A541 (P = 0.0337);Gain of phosphorylation at A541 (P = 0.0337);Gain of phosphorylation at A541 (P = 0.0337);Gain of phosphorylation at A541 (P = 0.0337);Gain of phosphorylation at A541 (P = 0.0337);Gain of phosphorylation at A541 (P = 0.0337);Gain of phosphorylation at A541 (P = 0.0337);Gain of phosphorylation at A541 (P = 0.0337);
MVP		0.55
MPC		0.68
ClinPred		0.17	T
GERP RS		4.6
Varity_R		0.29
gMVP		0.50

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: rs763169354; hg19: chr12-42858215;