rs144338942

Variant names:

• chr3-64153279-G-A
• rs144338942
• NM_198859.4:c.690C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_198859.4(PRICKLE2):​c.690C>T​(p.Gly230Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,614,164 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: PRICKLE2 NM_198859.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.15
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 3-64153279-G-A is Benign according to our data. Variant chr3-64153279-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 346476.
• BP7: Synonymous conserved (PhyloP=-2.15 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.690C>T	p.Gly230Gly	synonymous	Exon 6 of 8	NP_942559.1
	PRICKLE2	NM_001370528.1		c.690C>T	p.Gly230Gly	synonymous	Exon 6 of 8	NP_001357457.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE2	ENST00000638394.2	TSL:1 MANE Select	c.690C>T	p.Gly230Gly	synonymous	Exon 6 of 8	ENSP00000492363.1
	PRICKLE2	ENST00000295902.11	TSL:5	c.858C>T	p.Gly286Gly	synonymous	Exon 7 of 9	ENSP00000295902.7
	PRICKLE2	ENST00000906078.1		c.690C>T	p.Gly230Gly	synonymous	Exon 6 of 9	ENSP00000576137.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000501 AC: 126 AN: 251410 AF XY: 0.000589

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000269 AC: 393 AN: 1461864 Hom.: 3 Cov.: 31 AF XY: 0.000323 AC XY: 235 AN XY: 727234

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.00221 AC: 191 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000142 AC: 158 AN: 1111996

Other (OTH) AF: 0.000348 AC: 21 AN: 60392

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74464

African (AFR) AF: 0.000433 AC: 18 AN: 41572

American (AMR) AF: 0.000131 AC: 2 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68026

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.000242

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	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	-0.64
CADD	Benign	6.3
DANN	Benign	0.69
PhyloP100		-2.2
Mutation Taster		=97/3	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: rs144338942; hg19: chr3-64138955; COSMIC: COSV55763405;