3-64157181-C-T

Position:

• chr3-64157181-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000638394.2(PRICKLE2):​c.581G>A​(p.Arg194His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRICKLE2 ENST00000638394.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRICKLE2	NM_198859.4	c.581G>A	p.Arg194His	missense_variant	5/8	ENST00000638394.2	NP_942559.1
PRICKLE2	NM_001370528.1	c.581G>A	p.Arg194His	missense_variant	5/8		NP_001357457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRICKLE2	ENST00000638394.2	c.581G>A	p.Arg194His	missense_variant	5/8	1	NM_198859.4	ENSP00000492363
PRICKLE2	ENST00000295902.11	c.749G>A	p.Arg250His	missense_variant	6/9	5		ENSP00000295902	P1
PRICKLE2	ENST00000564377.6	c.581G>A	p.Arg194His	missense_variant	5/8	5		ENSP00000455004
PRICKLE2	ENST00000640303.1	n.1220G>A		non_coding_transcript_exon_variant	3/6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 194 of the PRICKLE2 protein (p.Arg194His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRICKLE2-related conditions. ClinVar contains an entry for this variant (Variation ID: 544244). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PRICKLE2 protein function with a positive predictive value of 80%. 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.7	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
REVEL	Pathogenic	0.82
Polyphen		1.0	D;D;.
MutPred		0.47		Gain of glycosylation at K192 (P = 0.1362);Gain of glycosylation at K192 (P = 0.1362);.;
MVP		0.97
MPC		1.6
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.67

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: rs1553644768; hg19: chr3-64142857;