rs144338942

Positions:

• chr3-64153279-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_198859.4(PRICKLE2):​c.690C>T​(p.Gly230=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,614,164 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 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: PRICKLE2 NM_198859.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.15

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 3-64153279-G-A is Benign according to our data. Variant chr3-64153279-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 346476.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=-2.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000282 (43/152300) while in subpopulation SAS AF= 0.00145 (7/4826). AF 95% confidence interval is 0.00068. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE2	NM_198859.4	c.690C>T	p.Gly230=	synonymous_variant	6/8	ENST00000638394.2
PRICKLE2	NM_001370528.1	c.690C>T	p.Gly230=	synonymous_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE2	ENST00000638394.2	c.690C>T	p.Gly230=	synonymous_variant	6/8	1	NM_198859.4

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000501 AC: 126 AN: 251410 Hom.: 0 AF XY: 0.000589 AC XY: 80 AN XY: 135878

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000269 AC: 393 AN: 1461864 Hom.: 3 Cov.: 31 AF XY: 0.000323 AC XY: 235 AN XY: 727234

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00221

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74464

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.000242

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Progressive myoclonic epilepsy Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Progressive myoclonic epilepsy type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.3
DANN	Benign	0.69

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: rs144338942; hg19: chr3-64138955; COSMIC: COSV55763405;