rs2306380

Positions:

• chr3-64160083-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198859.4(PRICKLE2):​c.259-6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 1,611,922 control chromosomes in the GnomAD database, including 112,681 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9551 hom., cov: 32)
  • Exomes 𝑓: 0.37 (103130 hom.)
• Consequence: PRICKLE2 NM_198859.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003360
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.27

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-64160083-T-C is Benign according to our data. Variant chr3-64160083-T-C is described in ClinVar as [Benign]. Clinvar id is 130033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-64160083-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRICKLE2	NM_198859.4	c.259-6A>G		splice_region_variant, intron_variant		ENST00000638394.2	NP_942559.1
PRICKLE2	NM_001370528.1	c.259-6A>G		splice_region_variant, intron_variant			NP_001357457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRICKLE2	ENST00000638394.2	c.259-6A>G		splice_region_variant, intron_variant		1	NM_198859.4	ENSP00000492363.1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53075 AN: 151884 Hom.: 9538 Cov.: 32

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.423

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.326

GnomAD3 exomes AF: 0.333 AC: 83680 AN: 251308 Hom.: 14784 AF XY: 0.340 AC XY: 46157 AN XY: 135848

Gnomad AFR exome AF: 0.314

Gnomad AMR exome AF: 0.179

Gnomad ASJ exome AF: 0.348

Gnomad EAS exome AF: 0.239

Gnomad SAS exome AF: 0.327

Gnomad FIN exome AF: 0.415

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.372 AC: 542466 AN: 1459920 Hom.: 103130 Cov.: 34 AF XY: 0.371 AC XY: 269805 AN XY: 726350

Gnomad4 AFR exome AF: 0.317

Gnomad4 AMR exome AF: 0.189

Gnomad4 ASJ exome AF: 0.345

Gnomad4 EAS exome AF: 0.203

Gnomad4 SAS exome AF: 0.324

Gnomad4 FIN exome AF: 0.411

Gnomad4 NFE exome AF: 0.390

Gnomad4 OTH exome AF: 0.360

GnomAD4 genome AF: 0.350 AC: 53131 AN: 152002 Hom.: 9551 Cov.: 32 AF XY: 0.349 AC XY: 25962 AN XY: 74322

Gnomad4 AFR AF: 0.317

Gnomad4 AMR AF: 0.254

Gnomad4 ASJ AF: 0.337

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.423

Gnomad4 NFE AF: 0.391

Gnomad4 OTH AF: 0.327

Alfa AF: 0.370 Hom.: 9820

Bravo AF: 0.334

Asia WGS AF: 0.288 AC: 1004 AN: 3478

EpiCase AF: 0.380

EpiControl AF: 0.377

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Progressive myoclonic epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Progressive myoclonic epilepsy type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.20
DANN	Benign	0.28

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs2306380; hg19: chr3-64145759; COSMIC: COSV55764238;