Genetic Variant PRICKLE2:c.*4733G>A (chr3-64094318-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198859.4(PRICKLE2):c.*4733G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.912 in 152,258 control chromosomes in the GnomAD database, including 64,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.91 ( 64508 hom., cov: 33)

Exomes 𝑓: 0.50 ( 0 hom. )

Consequence

PRICKLE2
NM_198859.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.02

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:):

PRICKLE2-AS1 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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 3-64094318-C-T is Benign according to our data. Variant chr3-64094318-C-T is described in ClinVar as [Benign]. Clinvar id is 346417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PRICKLE2	NM_198859.4 link	c.*4733G>A	3_prime_UTR_variant	Exon 8 of 8	ENST00000638394.2	NP_942559.1	Q7Z3G6A1LQZ3
PRICKLE2	NM_001370528.1 link	c.*4733G>A	3_prime_UTR_variant	Exon 8 of 8		NP_001357457.1
PRICKLE2-AS1	NR_045697.1 link	n.199-776C>T	intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRICKLE2	ENST00000638394 link	c.*4733G>A	3_prime_UTR_variant	Exon 8 of 8	1	NM_198859.4	ENSP00000492363.1	Q7Z3G6
PRICKLE2-AS1	ENST00000482609.1 link	n.199-776C>T	intron_variant	Intron 1 of 2	1
PRICKLE2	ENST00000295902 link	c.*4733G>A	3_prime_UTR_variant	Exon 9 of 9	5		ENSP00000295902.7	A0A1X7SBR1
PRICKLE2	ENST00000564377 link	c.*4733G>A	3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000455004.2	Q7Z3G6

Frequencies

GnomAD3 genomes

AF:

0.913

AC:

138859

AN:

152136

Hom.:

64485

Cov.:

show subpopulations

Gnomad AFR

AF:

0.720

Gnomad AMI

AF:

0.980

Gnomad AMR

AF:

0.960

Gnomad ASJ

AF:

0.993

Gnomad EAS

AF:

0.876

Gnomad SAS

AF:

0.984

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.953

Gnomad NFE

AF:

0.998

Gnomad OTH

AF:

0.932

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

Gnomad4 AFR exome

AF:

0.500

GnomAD4 genome

AF:

0.912

AC:

138924

AN:

152254

Hom.:

64508

Cov.:

AF XY:

0.914

AC XY:

67990

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.719

Gnomad4 AMR

AF:

0.960

Gnomad4 ASJ

AF:

0.993

Gnomad4 EAS

AF:

0.877

Gnomad4 SAS

AF:

0.984

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

0.998

Gnomad4 OTH

AF:

0.933

Alfa

AF:

0.975

Hom.:

60438

Bravo

AF:

0.899

Asia WGS

AF:

0.910

AC:

3165

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Progressive myoclonic epilepsy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

3.2

DANN

Benign

0.34

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