chr3-64157217-T-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198859.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE2	NM_198859.4	MANE Select	c.545A>T	p.Tyr182Phe	missense	Exon 5 of 8	NP_942559.1
	PRICKLE2	NM_001370528.1		c.545A>T	p.Tyr182Phe	missense	Exon 5 of 8	NP_001357457.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE2	ENST00000638394.2	TSL:1 MANE Select	c.545A>T	p.Tyr182Phe	missense	Exon 5 of 8	ENSP00000492363.1
	PRICKLE2	ENST00000295902.11	TSL:5	c.713A>T	p.Tyr238Phe	missense	Exon 6 of 9	ENSP00000295902.7
	PRICKLE2	ENST00000906078.1		c.545A>T	p.Tyr182Phe	missense	Exon 5 of 9	ENSP00000576137.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Progressive myoclonic epilepsy type 5 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.0
PrimateAI	Pathogenic	0.82	D
REVEL	Uncertain	0.59
Polyphen		0.58	P
MutPred		0.83		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
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs1553644782; hg19: chr3-64142893;