rs765119777

Variant names:

• chr12-42468780-G-A
• rs765119777
• NM_153026.3:c.434C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_153026.3(PRICKLE1):​c.434C>T​(p.Ala145Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A145T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 9.60
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE1	NM_153026.3	MANE Select	c.434C>T	p.Ala145Val	missense	Exon 5 of 8	NP_694571.2
	PRICKLE1	NM_001144881.2		c.434C>T	p.Ala145Val	missense	Exon 5 of 8	NP_001138353.1
	PRICKLE1	NM_001144882.2		c.434C>T	p.Ala145Val	missense	Exon 5 of 8	NP_001138354.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE1	ENST00000345127.9	TSL:1 MANE Select	c.434C>T	p.Ala145Val	missense	Exon 5 of 8	ENSP00000345064.3
	PRICKLE1	ENST00000445766.7	TSL:5	c.434C>T	p.Ala145Val	missense	Exon 5 of 8	ENSP00000398947.2
	PRICKLE1	ENST00000455697.6	TSL:5	c.434C>T	p.Ala145Val	missense	Exon 6 of 9	ENSP00000401060.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000875 AC: 22 AN: 251400 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461880 Hom.: 0 Cov.: 33 AF XY: 0.0000385 AC XY: 28 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74304

African (AFR) AF: 0.0000242 AC: 1 AN: 41402

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000282 Hom.: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Epilepsy, progressive myoclonic, 1B (2)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.9	L
PhyloP100		9.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.60
Sift	Benign	0.086	T
Sift4G	Benign	0.071	T
Polyphen		0.97	D
Vest4		0.87
MutPred		0.68		Loss of methylation at R144 (P = 0.1208)
MVP		0.80
MPC		1.0
ClinPred		0.40	T
GERP RS		5.6
Varity_R		0.19
gMVP		0.71
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs765119777; hg19: chr12-42862582; COSMIC: COSV61546909; COSMIC: COSV61546909;