rs2306380

Variant names:

• chr3-64160083-T-C
• rs2306380
• NM_198859.4:c.259-6A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000638394.2(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 ENST00000638394.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003360
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.27
• Publications: 14 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 130033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000638394.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE2	NM_198859.4	MANE Select	c.259-6A>G		splice_region intron	N/A	NP_942559.1
	PRICKLE2	NM_001370528.1		c.259-6A>G		splice_region intron	N/A	NP_001357457.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE2	ENST00000638394.2	TSL:1 MANE Select	c.259-6A>G		splice_region intron	N/A	ENSP00000492363.1
	PRICKLE2	ENST00000295902.11	TSL:5	c.427-6A>G		splice_region intron	N/A	ENSP00000295902.7
	PRICKLE2	ENST00000564377.6	TSL:5	c.259-6A>G		splice_region intron	N/A	ENSP00000455004.2

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

GnomAD2 exomes AF: 0.333 AC: 83680 AN: 251308 AF XY: 0.340

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 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

African (AFR) AF: 0.317 AC: 10611 AN: 33458

American (AMR) AF: 0.189 AC: 8438 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 9003 AN: 26130

East Asian (EAS) AF: 0.203 AC: 8039 AN: 39690

South Asian (SAS) AF: 0.324 AC: 27954 AN: 86216

European-Finnish (FIN) AF: 0.411 AC: 21862 AN: 53220

Middle Eastern (MID) AF: 0.330 AC: 1902 AN: 5766

European-Non Finnish (NFE) AF: 0.390 AC: 432957 AN: 1110382

Other (OTH) AF: 0.360 AC: 21700 AN: 60336

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

African (AFR) AF: 0.317 AC: 13126 AN: 41468

American (AMR) AF: 0.254 AC: 3882 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1167 AN: 3466

East Asian (EAS) AF: 0.228 AC: 1176 AN: 5152

South Asian (SAS) AF: 0.327 AC: 1575 AN: 4818

European-Finnish (FIN) AF: 0.423 AC: 4470 AN: 10558

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26601 AN: 67954

Other (OTH) AF: 0.327 AC: 689 AN: 2106

Alfa AF: 0.368 Hom.: 11266

Bravo AF: 0.334

Asia WGS AF: 0.288 AC: 1004 AN: 3478

EpiCase AF: 0.380

EpiControl AF: 0.377

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Progressive myoclonic epilepsy (1)
-	-	1	Progressive myoclonic epilepsy type 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.20
DANN	Benign	0.28
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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