3-64147708-A-G

Position:

• chr3-64147708-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000638394.2(PRICKLE2):​c.788-6T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,613,506 control chromosomes in the GnomAD database, including 9 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (9 hom.)
• Consequence: PRICKLE2 ENST00000638394.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001046
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.419

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 3-64147708-A-G is Benign according to our data. Variant chr3-64147708-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198631.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=2}. Variant chr3-64147708-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0014 (214/152348) while in subpopulation NFE AF= 0.00244 (166/68034). AF 95% confidence interval is 0.00214. There are 0 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 214 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRICKLE2	NM_198859.4	c.788-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000638394.2	NP_942559.1
PRICKLE2	NM_001370528.1	c.788-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001357457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRICKLE2	ENST00000638394.2	c.788-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_198859.4	ENSP00000492363

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00245

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00187 AC: 458 AN: 245262 Hom.: 1 AF XY: 0.00190 AC XY: 254 AN XY: 133334

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.000402

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000654

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00322

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00224 AC: 3272 AN: 1461158 Hom.: 9 Cov.: 35 AF XY: 0.00221 AC XY: 1607 AN XY: 726886

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000765

Gnomad4 FIN exome AF: 0.00283

Gnomad4 NFE exome AF: 0.00259

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00140 AC: 214 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.00144 AC XY: 107 AN XY: 74506

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00244

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00165 Hom.: 0

Bravo AF: 0.00118

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 11, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 21, 2015	- -

Progressive myoclonic epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Progressive myoclonic epilepsy type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.7
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.030		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: rs180903875; hg19: chr3-64133384;