rs141743294

Variant names:

• chr12-42472403-C-T
• rs141743294
• NM_153026.3:c.114G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-42472403-C-T
• chr12-42472403-C-A

Variant summary

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

The NM_153026.3(PRICKLE1):​c.114G>A​(p.Pro38Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,614,046 control chromosomes in the GnomAD database, including 31 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 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (30 hom.)
• Consequence: PRICKLE1 NM_153026.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -0.823
• Publications: 1 publications found

Genes affected

PRICKLE1 (HGNC:17019): (prickle planar cell polarity protein 1) This gene encodes a nuclear receptor that may be a negative regulator of the Wnt/beta-catenin signaling pathway. The encoded protein localizes to the nuclear membrane and has been implicated in the nuclear trafficking of the transcription repressors REST/NRSF and REST4. Mutations in this gene have been linked to progressive myoclonus epilepsy. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 3. [provided by RefSeq, Sep 2009]

PRICKLE1 Gene-Disease associations (from GenCC):

• epilepsy, progressive myoclonic, 1B

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Unverricht-Lundborg syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• progressive myoclonus epilepsy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 12-42472403-C-T is Benign according to our data. Variant chr12-42472403-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96505.
• BP7: Synonymous conserved (PhyloP=-0.823 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 30 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153026.3. 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
	PRICKLE1	NM_153026.3	MANE Select	c.114G>A	p.Pro38Pro	synonymous	Exon 2 of 8	NP_694571.2	Q96MT3
	PRICKLE1	NM_001144881.2		c.114G>A	p.Pro38Pro	synonymous	Exon 2 of 8	NP_001138353.1	Q96MT3
	PRICKLE1	NM_001144882.2		c.114G>A	p.Pro38Pro	synonymous	Exon 2 of 8	NP_001138354.1	Q96MT3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE1	ENST00000345127.9	TSL:1 MANE Select	c.114G>A	p.Pro38Pro	synonymous	Exon 2 of 8	ENSP00000345064.3	Q96MT3
	PRICKLE1	ENST00000547113.1	TSL:1	c.114G>A	p.Pro38Pro	synonymous	Exon 2 of 4	ENSP00000446699.1	F8W1Q8
	PRICKLE1	ENST00000640646.1	TSL:1	c.114G>A	p.Pro38Pro	synonymous	Exon 3 of 5	ENSP00000492483.1	F8W1Q8

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 439 AN: 152112 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00495

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00249 AC: 624 AN: 251022 AF XY: 0.00243

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.00413

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00386 AC: 5636 AN: 1461816 Hom.: 30 Cov.: 31 AF XY: 0.00375 AC XY: 2725 AN XY: 727212

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.000626 AC: 28 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00187 AC: 49 AN: 26136

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

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86256

European-Finnish (FIN) AF: 0.00350 AC: 187 AN: 53390

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

European-Non Finnish (NFE) AF: 0.00460 AC: 5118 AN: 1111976

Other (OTH) AF: 0.00343 AC: 207 AN: 60386

GnomAD4 genome AF: 0.00288 AC: 439 AN: 152230 Hom.: 1 Cov.: 32 AF XY: 0.00283 AC XY: 211 AN XY: 74428

African (AFR) AF: 0.000602 AC: 25 AN: 41538

American (AMR) AF: 0.00150 AC: 23 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00495 AC: 337 AN: 68014

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00357 Hom.: 2

Bravo AF: 0.00232

EpiCase AF: 0.00502

EpiControl AF: 0.00391

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	4	not specified (4)
-	-	1	Epilepsy, progressive myoclonic, 1B (1)
-	-	1	PRICKLE1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.14
DANN	Benign	0.52
PhyloP100		-0.82
Mutation Taster		=98/2	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: rs141743294; hg19: chr12-42866205; COSMIC: COSV61542010; COSMIC: COSV61542010;