rs1553644782

Variant names:

• chr3-64157217-T-A
• rs1553644782
• NM_198859.4:c.545A>T

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 rank	MANE	Protein	UniProt
PRICKLE2	NM_198859.4	c.545A>T	p.Tyr182Phe	missense_variant	Exon 5 of 8	ENST00000638394.2	NP_942559.1
PRICKLE2	NM_001370528.1	c.545A>T	p.Tyr182Phe	missense_variant	Exon 5 of 8		NP_001357457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRICKLE2	ENST00000638394.2	c.545A>T	p.Tyr182Phe	missense_variant	Exon 5 of 8	1	NM_198859.4	ENSP00000492363.1
PRICKLE2	ENST00000295902.11	c.713A>T	p.Tyr238Phe	missense_variant	Exon 6 of 9	5		ENSP00000295902.7
PRICKLE2	ENST00000564377.6	c.545A>T	p.Tyr182Phe	missense_variant	Exon 5 of 8	5		ENSP00000455004.2
PRICKLE2	ENST00000640303.1	n.1184A>T		non_coding_transcript_exon_variant	Exon 3 of 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

Sep 27, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PRICKLE2-related disease. 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"). 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. -

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
LIST_S2	Uncertain	0.90	.;D;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;.
PrimateAI	Pathogenic	0.82	D
REVEL	Uncertain	0.59
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;