rs139747674

chr3-64157305-C-T

Variant summary

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

The NM_198859.4(PRICKLE2):c.457G>A(p.Val153Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,614,084 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: PRICKLE2 NM_198859.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.19

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 (MetaRNN=0.009881824).
• BP6: Variant 3-64157305-C-T is Benign according to our data. Variant chr3-64157305-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242689.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, Likely_benign=1}. Variant chr3-64157305-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00119 (181/152336) while in subpopulation EAS AF= 0.00116 (6/5186). AF 95% confidence interval is 0.000795. There are 1 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 181 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE2	NM_198859.4	c.457G>A	p.Val153Ile	missense_variant	5/8	ENST00000638394.2
PRICKLE2	NM_001370528.1	c.457G>A	p.Val153Ile	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE2	ENST00000638394.2	c.457G>A	p.Val153Ile	missense_variant	5/8	1	NM_198859.4
PRICKLE2	ENST00000295902.11	c.625G>A	p.Val209Ile	missense_variant	6/9	5		P1
PRICKLE2	ENST00000564377.6	c.457G>A	p.Val153Ile	missense_variant	5/8	5
PRICKLE2	ENST00000640303.1	n.1096G>A		non_coding_transcript_exon_variant	3/6	5

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152220 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00696

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00131 AC: 328 AN: 250304 Hom.: 0 AF XY: 0.00117 AC XY: 158 AN XY: 135486

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00694

Gnomad NFE exome AF: 0.000913

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00108 AC: 1576 AN: 1461748 Hom.: 2 Cov.: 34 AF XY: 0.00102 AC XY: 742 AN XY: 727172

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00287

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00562

Gnomad4 NFE exome AF: 0.000926

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152336 Hom.: 1 Cov.: 33 AF XY: 0.00134 AC XY: 100 AN XY: 74502

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00696

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00104 Hom.: 1

Bravo AF: 0.000831

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00107 AC: 130

EpiCase AF: 0.000709

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

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

Apr 28, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 10, 2015

- -

Myoclonic epilepsy, progressive, X-linked Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 06, 2018

- -

Progressive myoclonic epilepsy type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0099	T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.33	T
Polyphen		0.0030	B;B;.
MVP		0.28
MPC		0.39
ClinPred		0.017	T
GERP RS		3.9
Varity_R		0.069
gMVP		0.20

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: rs139747674; hg19: chr3-64142981;