rs79087668

Variant names:

• chr12-42469464-C-T
• rs79087668
• NM_153026.3:c.370G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-42469464-C-T
• chr12-42469464-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153026.3(PRICKLE1):​c.370G>A​(p.Ala124Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00676 in 1,614,184 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A124A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0071 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (226 hom.)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:7
• Conservation: PhyloP100: 1.95
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001621902).
• BP6: Variant 12-42469464-C-T is Benign according to our data. Variant chr12-42469464-C-T is described in ClinVar as Benign. ClinVar VariationId is 130027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0843 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.370G>A	p.Ala124Thr	missense	Exon 4 of 8	NP_694571.2	Q96MT3
	PRICKLE1	NM_001144881.2		c.370G>A	p.Ala124Thr	missense	Exon 4 of 8	NP_001138353.1	Q96MT3
	PRICKLE1	NM_001144882.2		c.370G>A	p.Ala124Thr	missense	Exon 4 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.370G>A	p.Ala124Thr	missense	Exon 4 of 8	ENSP00000345064.3	Q96MT3
	PRICKLE1	ENST00000445766.7	TSL:5	c.370G>A	p.Ala124Thr	missense	Exon 4 of 8	ENSP00000398947.2	Q96MT3
	PRICKLE1	ENST00000455697.6	TSL:5	c.370G>A	p.Ala124Thr	missense	Exon 5 of 9	ENSP00000401060.1	Q96MT3

Frequencies

GnomAD3 genomes AF: 0.00709 AC: 1080 AN: 152226 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0920

Gnomad SAS AF: 0.0370

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00267

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.0141 AC: 3542 AN: 251392 AF XY: 0.0140

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.0955

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00717

GnomAD4 exome AF: 0.00673 AC: 9839 AN: 1461840 Hom.: 226 Cov.: 32 AF XY: 0.00734 AC XY: 5341 AN XY: 727228

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.0158 AC: 705 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 56 AN: 26134

East Asian (EAS) AF: 0.0834 AC: 3312 AN: 39700

South Asian (SAS) AF: 0.0265 AC: 2287 AN: 86258

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53380

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.00255 AC: 2833 AN: 1112008

Other (OTH) AF: 0.00970 AC: 586 AN: 60390

GnomAD4 genome AF: 0.00708 AC: 1079 AN: 152344 Hom.: 44 Cov.: 32 AF XY: 0.00819 AC XY: 610 AN XY: 74498

African (AFR) AF: 0.000745 AC: 31 AN: 41586

American (AMR) AF: 0.0122 AC: 187 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.0910 AC: 472 AN: 5184

South Asian (SAS) AF: 0.0373 AC: 180 AN: 4828

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00268 AC: 182 AN: 68032

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00674 Hom.: 83

Bravo AF: 0.00841

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.0135 AC: 1644

Asia WGS AF: 0.0530 AC: 185 AN: 3478

EpiCase AF: 0.00327

EpiControl AF: 0.00302

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Epilepsy, progressive myoclonic, 1B (1)
-	-	1	not provided (1)
1	-	-	Self-limited epilepsy with centrotemporal spikes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.0089
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.84	L
PhyloP100		1.9
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.099
Sift	Benign	0.18	T
Sift4G	Benign	0.26	T
Polyphen		0.0020	B
Vest4		0.078
MPC		0.34
ClinPred		0.0076	T
GERP RS		3.5
Varity_R		0.087
gMVP		0.31
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79087668; hg19: chr12-42863266; COSMIC: COSV61543587; COSMIC: COSV61543587;