Genetic Variant PRICKLE1:p.Met471Lys (chr12-42464622-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_153026.3(PRICKLE1):c.1412T>A(p.Met471Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M471T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PRICKLE1
NM_153026.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.87

Publications

0 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRICKLE1	NM_153026.3 link	c.1412T>A	p.Met471Lys	missense_variant	Exon 7 of 8	ENST00000345127.9	NP_694571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRICKLE1	ENST00000345127.9 link	c.1412T>A	p.Met471Lys	missense_variant	Exon 7 of 8	1	NM_153026.3	ENSP00000345064.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

T;T;T;T;T;T;T;T;T;T

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;.;.;.;.;.;.;.;.;D

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.59

D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.0

L;L;L;L;L;L;L;L;L;L

PhyloP100

8.9

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.4

N;.;N;.;N;.;.;N;.;N

REVEL

Uncertain

0.40

Sift

Benign

0.26

T;.;T;.;T;.;.;T;.;T

Sift4G

Benign

0.81

T;.;T;.;T;.;.;T;.;T

Polyphen

0.83

P;P;P;P;P;P;P;P;P;P

Vest4

0.88

MutPred

0.47

Gain of ubiquitination at M471 (P = 0.0109);Gain of ubiquitination at M471 (P = 0.0109);Gain of ubiquitination at M471 (P = 0.0109);Gain of ubiquitination at M471 (P = 0.0109);Gain of ubiquitination at M471 (P = 0.0109);Gain of ubiquitination at M471 (P = 0.0109);Gain of ubiquitination at M471 (P = 0.0109);Gain of ubiquitination at M471 (P = 0.0109);Gain of ubiquitination at M471 (P = 0.0109);Gain of ubiquitination at M471 (P = 0.0109);

MVP

0.62

MPC

1.2

ClinPred

0.85

GERP RS

5.8

Varity_R

0.69

gMVP

0.49

Mutation Taster

=47/53

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over