rs1553644782

Positions:

• chr3-64157217-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_198859.4(PRICKLE2):​c.545A>T​(p.Tyr182Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRICKLE2 NM_198859.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.02

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE2	NM_198859.4	c.545A>T	p.Tyr182Phe	missense_variant	5/8	ENST00000638394.2
PRICKLE2	NM_001370528.1	c.545A>T	p.Tyr182Phe	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE2	ENST00000638394.2	c.545A>T	p.Tyr182Phe	missense_variant	5/8	1	NM_198859.4
PRICKLE2	ENST00000295902.11	c.713A>T	p.Tyr238Phe	missense_variant	6/9	5		P1
PRICKLE2	ENST00000564377.6	c.545A>T	p.Tyr182Phe	missense_variant	5/8	5
PRICKLE2	ENST00000640303.1	n.1184A>T		non_coding_transcript_exon_variant	3/6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive myoclonic epilepsy type 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with PRICKLE2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with phenylalanine at codon 182 of the PRICKLE2 protein (p.Tyr182Phe). The tyrosine residue is highly conserved and there is a small physicochemical difference between tyrosine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.75	D;D;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
Polyphen		0.58	P;P;.
MutPred		0.83		Gain of methylation at K180 (P = 0.0619);Gain of methylation at K180 (P = 0.0619);.;
MVP		0.75
MPC		0.62
ClinPred		0.93	D
GERP RS		5.8
Varity_R		0.47
gMVP		0.60

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: rs1553644782; hg19: chr3-64142893;