rs200220646

chr3-64099483-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_198859.4(PRICKLE2):c.2103G>T(p.Leu701=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000333 in 1,587,990 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (3 hom.)
• Consequence: PRICKLE2 NM_198859.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.58

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-AS1 (HGNC:40916): (PRICKLE2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 3-64099483-C-A is Benign according to our data. Variant chr3-64099483-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281799.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=2}.
• BP7: Synonymous conserved (PhyloP=1.58 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000217 (33/152346) while in subpopulation SAS AF= 0.00166 (8/4828). AF 95% confidence interval is 0.000824. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE2	NM_198859.4	c.2103G>T	p.Leu701=	synonymous_variant	8/8	ENST00000638394.2
PRICKLE2-AS1	NR_045697.1	n.2857C>A		non_coding_transcript_exon_variant	3/3
PRICKLE2	NM_001370528.1	c.2103G>T	p.Leu701=	synonymous_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE2	ENST00000638394.2	c.2103G>T	p.Leu701=	synonymous_variant	8/8	1	NM_198859.4
PRICKLE2-AS1	ENST00000476308.1	n.211C>A		non_coding_transcript_exon_variant	1/2	2
PRICKLE2-AS1	ENST00000482609.1	n.2857C>A		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000504 AC: 121 AN: 240054 Hom.: 1 AF XY: 0.000649 AC XY: 84 AN XY: 129354

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.0000901

Gnomad ASJ exome AF: 0.00127

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00254

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.00105

GnomAD4 exome AF: 0.000345 AC: 496 AN: 1435644 Hom.: 3 Cov.: 31 AF XY: 0.000433 AC XY: 307 AN XY: 709558

Gnomad4 AFR exome AF: 0.0000610

Gnomad4 AMR exome AF: 0.0000232

Gnomad4 ASJ exome AF: 0.000929

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00262

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.000526

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74498

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000396 Hom.: 1

Bravo AF: 0.000174

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 30, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	PRICKLE2: BP4, BP7 -

Progressive myoclonic epilepsy Uncertain:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Progressive myoclonic epilepsy type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	17
Dann	Benign	0.95

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

Other links and lift over

dbSNP: rs200220646; hg19: chr3-64085159;