rs113542442

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_198859.4(PRICKLE2):c.2433C>G(p.His811Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000743 in 1,614,088 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000053 ( 1 hom. )

Consequence

PRICKLE2
NM_198859.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.59

Variant links:

Genes affected

PRICKLE2 (HGNC:20340): (prickle planar cell polarity protein 2) This gene encodes a homolog of Drosophila prickle. The exact function of this gene is not known, however, studies in mice suggest that it may be involved in seizure prevention. Mutations in this gene are associated with progressive myoclonic epilepsy type 5. [provided by RefSeq, Dec 2011]

PRICKLE2 links:

PRICKLE2-AS1 (HGNC:40916): (PRICKLE2 antisense RNA 1)

PRICKLE2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2920912).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000283 (43/152208) while in subpopulation AFR AF= 0.000965 (40/41462). AF 95% confidence interval is 0.000728. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PRICKLE2	NM_198859.4 linkuse as main transcript	c.2433C>G	p.His811Gln	missense_variant	8/8	ENST00000638394.2
PRICKLE2-AS1	NR_045697.1 linkuse as main transcript	n.2527G>C		non_coding_transcript_exon_variant	3/3
PRICKLE2	NM_001370528.1 linkuse as main transcript	c.2433C>G	p.His811Gln	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE2	ENST00000638394.2 linkuse as main transcript	c.2433C>G	p.His811Gln	missense_variant	8/8	1	NM_198859.4
PRICKLE2-AS1	ENST00000482609.1 linkuse as main transcript	n.2527G>C		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251478

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000527

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00146

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000283

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.000965

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000452

Hom.:

Bravo

AF:

0.000359

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2022

The c.2433C>G (p.H811Q) alteration is located in exon 8 (coding exon 7) of the PRICKLE2 gene. This alteration results from a C to G substitution at nucleotide position 2433, causing the histidine (H) at amino acid position 811 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 21, 2021

- -

Progressive myoclonic epilepsy type 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 811 of the PRICKLE2 protein (p.His811Gln). This variant is present in population databases (rs113542442, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PRICKLE2-related conditions. ClinVar contains an entry for this variant (Variation ID: 578987). 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 PRICKLE2 protein function with a negative predictive value of 80%. 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

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.11

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.28

T;T;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.92

M_CAP

Benign

0.034

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

1.6

L;L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

Polyphen

0.99

D;D;.

MutPred

0.43

Gain of relative solvent accessibility (P = 0.0999);Gain of relative solvent accessibility (P = 0.0999);.;

MVP

0.81

MPC

0.55

ClinPred

0.077

GERP RS

4.8

Varity_R

0.18

gMVP

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over