Genetic Variant NM_153026.3:c.1414T>C (chr12-42464620-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

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

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 8.87

Publications

6 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

epilepsy, progressive myoclonic, 1B
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Unverricht-Lundborg syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
progressive myoclonus epilepsy
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PRICKLE1 links:

ENSG00000257225 (HGNC:58444):

ENSG00000257225 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 VariationId is 30730.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153026.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRICKLE1	NM_153026.3	MANE Select	c.1414T>C	p.Tyr472His	missense	Exon 7 of 8	NP_694571.2
PRICKLE1	NM_001144881.2		c.1414T>C	p.Tyr472His	missense	Exon 7 of 8	NP_001138353.1
PRICKLE1	NM_001144882.2		c.1414T>C	p.Tyr472His	missense	Exon 7 of 8	NP_001138354.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRICKLE1	ENST00000345127.9	TSL:1 MANE Select	c.1414T>C	p.Tyr472His	missense	Exon 7 of 8	ENSP00000345064.3
ENSG00000257225	ENST00000547824.1	TSL:1	n.1364-81A>G		intron	N/A
PRICKLE1	ENST00000445766.7	TSL:5	c.1414T>C	p.Tyr472His	missense	Exon 7 of 8	ENSP00000398947.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Epilepsy, progressive myoclonic, 1B

Pathogenic:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Feb 11, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.67

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.0

PhyloP100

8.9

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.47

Sift

Uncertain

0.0030

Sift4G

Benign

0.25

Polyphen

1.0

Vest4

0.85

MutPred

0.49

Loss of phosphorylation at Y472 (P = 0.0264)

MVP

0.68

MPC

1.3

ClinPred

0.81

GERP RS

5.8

Varity_R

0.49

gMVP

0.37

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over