Genetic Variant PRICKLE2:p.Gly152Arg (chr3-64157308-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_198859.4(PRICKLE2):c.454G>C(p.Gly152Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. G152S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

PRICKLE2
NM_198859.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.02

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

PRICKLE2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.892

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRICKLE2	NM_198859.4 link	c.454G>C	p.Gly152Arg	missense_variant	Exon 5 of 8	ENST00000638394.2	NP_942559.1
PRICKLE2	NM_001370528.1 link	c.454G>C	p.Gly152Arg	missense_variant	Exon 5 of 8		NP_001357457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PRICKLE2	ENST00000638394.2 link	c.454G>C	p.Gly152Arg	missense_variant	Exon 5 of 8	1	NM_198859.4	ENSP00000492363.1
PRICKLE2	ENST00000295902.11 link	c.622G>C	p.Gly208Arg	missense_variant	Exon 6 of 9	5		ENSP00000295902.7
PRICKLE2	ENST00000564377.6 link	c.454G>C	p.Gly152Arg	missense_variant	Exon 5 of 8	5		ENSP00000455004.2
PRICKLE2	ENST00000640303.1 link	n.1093G>C		non_coding_transcript_exon_variant	Exon 3 of 6	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

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:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1111998

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D;D;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

.;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.1

M;M;.

PhyloP100

5.0

PrimateAI

Uncertain

0.76

REVEL

Uncertain

0.62

Polyphen

0.79

P;P;.

MutPred

0.73

Loss of catalytic residue at V153 (P = 0.0297);Loss of catalytic residue at V153 (P = 0.0297);.;

MVP

0.85

MPC

1.3

ClinPred

0.99

GERP RS

5.7

Varity_R

0.59

gMVP

0.64

Mutation Taster

=63/37

polymorphism

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over