12-42460406-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_153026.3(PRICKLE1):​c.1899T>C​(p.Phe633Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,613,382 control chromosomes in the GnomAD database, including 104,864 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8241 hom., cov: 31)
Exomes 𝑓: 0.36 ( 96623 hom. )

Consequence

PRICKLE1
NM_153026.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.436
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.58).
BP6
Variant 12-42460406-A-G is Benign according to our data. Variant chr12-42460406-A-G is described in ClinVar as [Benign]. Clinvar id is 130024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-42460406-A-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.436 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRICKLE1NM_153026.3 linkc.1899T>C p.Phe633Phe synonymous_variant Exon 8 of 8 ENST00000345127.9 NP_694571.2 Q96MT3A0A024R0W7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRICKLE1ENST00000345127.9 linkc.1899T>C p.Phe633Phe synonymous_variant Exon 8 of 8 1 NM_153026.3 ENSP00000345064.3 Q96MT3

Frequencies

GnomAD3 genomes
AF:
0.320
AC:
48517
AN:
151562
Hom.:
8233
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.204
Gnomad AMI
AF:
0.380
Gnomad AMR
AF:
0.342
Gnomad ASJ
AF:
0.374
Gnomad EAS
AF:
0.268
Gnomad SAS
AF:
0.252
Gnomad FIN
AF:
0.381
Gnomad MID
AF:
0.385
Gnomad NFE
AF:
0.381
Gnomad OTH
AF:
0.324
GnomAD3 exomes
AF:
0.349
AC:
87749
AN:
251368
Hom.:
15874
AF XY:
0.348
AC XY:
47223
AN XY:
135854
show subpopulations
Gnomad AFR exome
AF:
0.198
Gnomad AMR exome
AF:
0.406
Gnomad ASJ exome
AF:
0.382
Gnomad EAS exome
AF:
0.269
Gnomad SAS exome
AF:
0.257
Gnomad FIN exome
AF:
0.385
Gnomad NFE exome
AF:
0.380
Gnomad OTH exome
AF:
0.366
GnomAD4 exome
AF:
0.360
AC:
526194
AN:
1461700
Hom.:
96623
Cov.:
47
AF XY:
0.358
AC XY:
260349
AN XY:
727156
show subpopulations
Gnomad4 AFR exome
AF:
0.204
Gnomad4 AMR exome
AF:
0.397
Gnomad4 ASJ exome
AF:
0.384
Gnomad4 EAS exome
AF:
0.293
Gnomad4 SAS exome
AF:
0.255
Gnomad4 FIN exome
AF:
0.392
Gnomad4 NFE exome
AF:
0.372
Gnomad4 OTH exome
AF:
0.349
GnomAD4 genome
AF:
0.320
AC:
48551
AN:
151682
Hom.:
8241
Cov.:
31
AF XY:
0.318
AC XY:
23558
AN XY:
74110
show subpopulations
Gnomad4 AFR
AF:
0.204
Gnomad4 AMR
AF:
0.343
Gnomad4 ASJ
AF:
0.374
Gnomad4 EAS
AF:
0.267
Gnomad4 SAS
AF:
0.252
Gnomad4 FIN
AF:
0.381
Gnomad4 NFE
AF:
0.381
Gnomad4 OTH
AF:
0.322
Alfa
AF:
0.359
Hom.:
5144
Bravo
AF:
0.318
Asia WGS
AF:
0.262
AC:
914
AN:
3478
EpiCase
AF:
0.377
EpiControl
AF:
0.379

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Jan 08, 2016
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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. -

-
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jul 02, 2014
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:3
May 07, 2018
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Epilepsy, progressive myoclonic, 1B Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.58
CADD
Benign
7.2
DANN
Benign
0.66

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs3747563; hg19: chr12-42854208; COSMIC: COSV58203830; COSMIC: COSV58203830; API