rs281865564

Positions:

• chr12-42464620-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_153026.3(PRICKLE1):​c.1414T>C​(p.Tyr472His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.87

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-42464620-A-G is Pathogenic according to our data. Variant chr12-42464620-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 30730.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-42464620-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE1	NM_153026.3	c.1414T>C	p.Tyr472His	missense_variant	7/8	ENST00000345127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.1414T>C	p.Tyr472His	missense_variant	7/8	1	NM_153026.3	P1
	ENST00000547824.1	n.1364-81A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Epilepsy, progressive myoclonic, 1B Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 11, 2011	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;T;T;T;T;T;T;T;T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;.;.;.;.;.;.;.;.;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.0	L;L;L;L;L;L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.1	N;.;N;.;N;.;.;N;.;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D;.;D;.;D;.;.;D;.;D
Sift4G	Benign	0.25	T;.;T;.;T;.;.;T;.;T
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D
Vest4		0.85
MutPred		0.49		Loss of phosphorylation at Y472 (P = 0.0264);Loss of phosphorylation at Y472 (P = 0.0264);Loss of phosphorylation at Y472 (P = 0.0264);Loss of phosphorylation at Y472 (P = 0.0264);Loss of phosphorylation at Y472 (P = 0.0264);Loss of phosphorylation at Y472 (P = 0.0264);Loss of phosphorylation at Y472 (P = 0.0264);Loss of phosphorylation at Y472 (P = 0.0264);Loss of phosphorylation at Y472 (P = 0.0264);Loss of phosphorylation at Y472 (P = 0.0264);
MVP		0.68
MPC		1.3
ClinPred		0.81	D
GERP RS		5.8
Varity_R		0.49
gMVP		0.37

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: rs281865564; hg19: chr12-42858422;