3-64147708-A-G

Variant names:

• chr3-64147708-A-G
• rs180903875
• NM_198859.4:c.788-6T>C

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.788-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,613,506 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (9 hom.)
• Consequence: PRICKLE2 NM_198859.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001046
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.419
• Publications: 1 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 (BayesDel_noAF=-0.91).
• BP6: Variant 3-64147708-A-G is Benign according to our data. Variant chr3-64147708-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198631.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR,AD 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.788-6T>C		splice_region intron	N/A	NP_942559.1	Q7Z3G6
	PRICKLE2	NM_001370528.1		c.788-6T>C		splice_region intron	N/A	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.788-6T>C		splice_region intron	N/A	ENSP00000492363.1	Q7Z3G6
	PRICKLE2	ENST00000295902.11	TSL:5	c.956-6T>C		splice_region intron	N/A	ENSP00000295902.7	A0A1X7SBR1
	PRICKLE2	ENST00000906078.1		c.788-6T>C		splice_region intron	N/A	ENSP00000576137.1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00245

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00187 AC: 458 AN: 245262 AF XY: 0.00190

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.000402

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00322

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00224 AC: 3272 AN: 1461158 Hom.: 9 Cov.: 35 AF XY: 0.00221 AC XY: 1607 AN XY: 726886

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000671 AC: 30 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000765 AC: 66 AN: 86258

European-Finnish (FIN) AF: 0.00283 AC: 149 AN: 52730

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00259 AC: 2883 AN: 1111972

Other (OTH) AF: 0.00192 AC: 116 AN: 60390

GnomAD4 genome AF: 0.00140 AC: 214 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.00144 AC XY: 107 AN XY: 74506

African (AFR) AF: 0.000385 AC: 16 AN: 41586

American (AMR) AF: 0.000653 AC: 10 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00244 AC: 166 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00118

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Progressive myoclonic epilepsy (1)
-	-	1	Progressive myoclonic epilepsy type 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.7
DANN	Benign	0.49
PhyloP100		0.42
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.030		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: rs180903875; hg19: chr3-64133384;