12-42464674-C-T

Variant names:

• chr12-42464674-C-T
• rs748454609
• NM_153026.3:c.1360G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_153026.3(PRICKLE1):​c.1360G>A​(p.Glu454Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E454E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.54
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13026717).
• BP6: Variant 12-42464674-C-T is Benign according to our data. Variant chr12-42464674-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206667.

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.1360G>A	p.Glu454Lys	missense	Exon 7 of 8	NP_694571.2
	PRICKLE1	NM_001144881.2		c.1360G>A	p.Glu454Lys	missense	Exon 7 of 8	NP_001138353.1
	PRICKLE1	NM_001144882.2		c.1360G>A	p.Glu454Lys	missense	Exon 7 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.1360G>A	p.Glu454Lys	missense	Exon 7 of 8	ENSP00000345064.3
	ENSG00000257225	ENST00000547824.1	TSL:1	n.1364-27C>T		intron	N/A
	PRICKLE1	ENST00000445766.7	TSL:5	c.1360G>A	p.Glu454Lys	missense	Exon 7 of 8	ENSP00000398947.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251320 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

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

American (AMR) AF: 0.0000224 AC: 1 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: 86256

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112010

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Epilepsy, progressive myoclonic, 1B Uncertain:1

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 454 of the PRICKLE1 protein (p.Glu454Lys). This variant is present in population databases (rs748454609, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with PRICKLE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 206667). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRICKLE1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

not provided Uncertain:1

Dec 16, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Glu454Lys (GAG>AAG): c.1360 G>A in exon 7 of the PRICKLE1 gene (NM_153026.2). The E454K variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E454K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).

not specified Benign:1

Sep 27, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.77
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.086
Sift	Benign	0.71	T
Sift4G	Benign	0.92	T
Polyphen		0.76	P
Vest4		0.32
MutPred		0.32		Gain of MoRF binding (P = 0.0041)
MVP		0.32
MPC		0.42
ClinPred		0.18	T
GERP RS		3.8
Varity_R		0.14
gMVP		0.21
Mutation Taster		=95/5	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: rs748454609; hg19: chr12-42858476; COSMIC: COSV58204414; COSMIC: COSV58204414;