chr3-64157305-C-T

Variant names:

• chr3-64157305-C-T
• rs139747674
• NM_198859.4:c.457G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 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. 14/20 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
• Publications: 10 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: Benign. The variant received -9 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 VariationId is 242689.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE2	NM_198859.4	MANE Select	c.457G>A	p.Val153Ile	missense	Exon 5 of 8	NP_942559.1	Q7Z3G6
	PRICKLE2	NM_001370528.1		c.457G>A	p.Val153Ile	missense	Exon 5 of 8	NP_001357457.1	Q7Z3G6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE2	ENST00000638394.2	TSL:1 MANE Select	c.457G>A	p.Val153Ile	missense	Exon 5 of 8	ENSP00000492363.1	Q7Z3G6
	PRICKLE2	ENST00000295902.11	TSL:5	c.625G>A	p.Val209Ile	missense	Exon 6 of 9	ENSP00000295902.7	A0A1X7SBR1
	PRICKLE2	ENST00000906078.1		c.457G>A	p.Val153Ile	missense	Exon 5 of 9	ENSP00000576137.1

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

GnomAD2 exomes AF: 0.00131 AC: 328 AN: 250304 AF XY: 0.00117

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 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

African (AFR) AF: 0.000179 AC: 6 AN: 33472

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 75 AN: 26136

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39700

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86250

European-Finnish (FIN) AF: 0.00562 AC: 300 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.000926 AC: 1030 AN: 1112002

Other (OTH) AF: 0.00167 AC: 101 AN: 60388

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

African (AFR) AF: 0.000120 AC: 5 AN: 41574

American (AMR) AF: 0.00111 AC: 17 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00696 AC: 74 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000938 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Myoclonic epilepsy, progressive, X-linked (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	1	-	Progressive myoclonic epilepsy (1)
-	-	1	Progressive myoclonic epilepsy type 5 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.2
PrimateAI	Benign	0.33	T
REVEL	Benign	0.21
Polyphen		0.0030	B
MVP		0.28
MPC		0.39
ClinPred		0.017	T
GERP RS		3.9
Varity_R		0.069
gMVP		0.20
Mutation Taster		=99/1	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: rs139747674; hg19: chr3-64142981;