rs74081707

Variant names:

• chr12-42468629-G-A
• rs74081707
• NM_153026.3:c.585C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_153026.3(PRICKLE1):​c.585C>T​(p.Asp195Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00534 in 1,613,408 control chromosomes in the GnomAD database, including 409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (224 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (185 hom.)
• Consequence: PRICKLE1 NM_153026.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0260
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 12-42468629-G-A is Benign according to our data. Variant chr12-42468629-G-A is described in ClinVar as Benign. ClinVar VariationId is 130029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.026 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0971 is higher than 0.05.

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.585C>T	p.Asp195Asp	synonymous	Exon 5 of 8	NP_694571.2	Q96MT3
	PRICKLE1	NM_001144881.2		c.585C>T	p.Asp195Asp	synonymous	Exon 5 of 8	NP_001138353.1	Q96MT3
	PRICKLE1	NM_001144882.2		c.585C>T	p.Asp195Asp	synonymous	Exon 5 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.585C>T	p.Asp195Asp	synonymous	Exon 5 of 8	ENSP00000345064.3	Q96MT3
	PRICKLE1	ENST00000445766.7	TSL:5	c.585C>T	p.Asp195Asp	synonymous	Exon 5 of 8	ENSP00000398947.2	Q96MT3
	PRICKLE1	ENST00000455697.6	TSL:5	c.585C>T	p.Asp195Asp	synonymous	Exon 6 of 9	ENSP00000401060.1	Q96MT3

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4336 AN: 151820 Hom.: 224 Cov.: 32

Gnomad AFR AF: 0.0999

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00944

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0240

GnomAD2 exomes AF: 0.00731 AC: 1834 AN: 250974 AF XY: 0.00513

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.00442

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00292 AC: 4271 AN: 1461470 Hom.: 185 Cov.: 33 AF XY: 0.00254 AC XY: 1847 AN XY: 727048

African (AFR) AF: 0.103 AC: 3430 AN: 33462

American (AMR) AF: 0.00467 AC: 209 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00264 AC: 15 AN: 5684

European-Non Finnish (NFE) AF: 0.000194 AC: 216 AN: 1111772

Other (OTH) AF: 0.00613 AC: 370 AN: 60350

GnomAD4 genome AF: 0.0286 AC: 4338 AN: 151938 Hom.: 224 Cov.: 32 AF XY: 0.0271 AC XY: 2012 AN XY: 74270

African (AFR) AF: 0.0997 AC: 4127 AN: 41408

American (AMR) AF: 0.00943 AC: 144 AN: 15270

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67980

Other (OTH) AF: 0.0238 AC: 50 AN: 2104

Alfa AF: 0.0143 Hom.: 68

Bravo AF: 0.0326

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.9
DANN	Benign	0.84
PhyloP100		0.026
Mutation Taster		=88/12	polymorphism (auto)

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: rs74081707; hg19: chr12-42862431;