rs1555229335

Variant names:

• chr12-42460293-T-A
• rs1555229335
• NM_153026.3:c.2012A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153026.3(PRICKLE1):​c.2012A>T​(p.His671Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.00
• Publications: 0 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

ENSG00000257225 (HGNC:58444):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24661788).

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.2012A>T	p.His671Leu	missense	Exon 8 of 8	NP_694571.2
	PRICKLE1	NM_001144881.2		c.2012A>T	p.His671Leu	missense	Exon 8 of 8	NP_001138353.1
	PRICKLE1	NM_001144882.2		c.2012A>T	p.His671Leu	missense	Exon 8 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.2012A>T	p.His671Leu	missense	Exon 8 of 8	ENSP00000345064.3
	ENSG00000257225	ENST00000547824.1	TSL:1	n.928T>A		non_coding_transcript_exon	Exon 1 of 2
	PRICKLE1	ENST00000445766.7	TSL:5	c.2012A>T	p.His671Leu	missense	Exon 8 of 8	ENSP00000398947.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461890 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Epilepsy, progressive myoclonic, 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.40	T
Eigen	Benign	0.076
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.0
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.023	D
Polyphen		0.044	B
Vest4		0.30
MutPred		0.14		Loss of methylation at R666 (P = 0.1556)
MVP		0.60
MPC		0.67
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.48
gMVP		0.35
Mutation Taster		=94/6	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: rs1555229335; hg19: chr12-42854095;