rs1055556905

Positions:

• chr12-42460650-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153026.3(PRICKLE1):​c.1655G>A​(p.Gly552Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24399793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE1	NM_153026.3	c.1655G>A	p.Gly552Glu	missense_variant	8/8	ENST00000345127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.1655G>A	p.Gly552Glu	missense_variant	8/8	1	NM_153026.3	P1
	ENST00000547824.1	n.1285C>T		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Invitae

Aug 30, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRICKLE1 protein function. ClinVar contains an entry for this variant (Variation ID: 469507). This variant has not been reported in the literature in individuals affected with PRICKLE1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 552 of the PRICKLE1 protein (p.Gly552Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T
Eigen	Benign	0.010
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.0	M;M;M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.5	N;.;N;.;N;.;.;N;.;N
REVEL	Benign	0.29
Sift	Uncertain	0.0020	D;.;D;.;D;.;.;D;.;D
Sift4G	Uncertain	0.014	D;.;D;.;D;.;.;D;.;D
Polyphen		0.075	B;B;B;B;B;B;B;B;B;B
Vest4		0.17
MutPred		0.14		Gain of phosphorylation at S549 (P = 0.1348);Gain of phosphorylation at S549 (P = 0.1348);Gain of phosphorylation at S549 (P = 0.1348);Gain of phosphorylation at S549 (P = 0.1348);Gain of phosphorylation at S549 (P = 0.1348);Gain of phosphorylation at S549 (P = 0.1348);Gain of phosphorylation at S549 (P = 0.1348);Gain of phosphorylation at S549 (P = 0.1348);Gain of phosphorylation at S549 (P = 0.1348);Gain of phosphorylation at S549 (P = 0.1348);
MVP		0.36
MPC		0.49
ClinPred		0.83	D
GERP RS		4.7
Varity_R		0.64
gMVP		0.49

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: rs1055556905; hg19: chr12-42854452;