rs113542442
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2
The NM_198859.4(PRICKLE2):āc.2433C>Gā(p.His811Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000743 in 1,614,088 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00028 ( 0 hom., cov: 33)
Exomes š: 0.000053 ( 1 hom. )
Consequence
PRICKLE2
NM_198859.4 missense
NM_198859.4 missense
Scores
7
9
Clinical Significance
Conservation
PhyloP100: 4.59
Genes affected
PRICKLE2 (HGNC:20340): (prickle planar cell polarity protein 2) This gene encodes a homolog of Drosophila prickle. The exact function of this gene is not known, however, studies in mice suggest that it may be involved in seizure prevention. Mutations in this gene are associated with progressive myoclonic epilepsy type 5. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.2920912).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000283 (43/152208) while in subpopulation AFR AF= 0.000965 (40/41462). AF 95% confidence interval is 0.000728. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 43 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRICKLE2 | NM_198859.4 | c.2433C>G | p.His811Gln | missense_variant | 8/8 | ENST00000638394.2 | |
PRICKLE2-AS1 | NR_045697.1 | n.2527G>C | non_coding_transcript_exon_variant | 3/3 | |||
PRICKLE2 | NM_001370528.1 | c.2433C>G | p.His811Gln | missense_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRICKLE2 | ENST00000638394.2 | c.2433C>G | p.His811Gln | missense_variant | 8/8 | 1 | NM_198859.4 | ||
PRICKLE2-AS1 | ENST00000482609.1 | n.2527G>C | non_coding_transcript_exon_variant | 3/3 | 1 |
Frequencies
GnomAD3 genomes AF: 0.000283 AC: 43AN: 152208Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251478Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135910
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GnomAD4 exome AF: 0.0000527 AC: 77AN: 1461880Hom.: 1 Cov.: 31 AF XY: 0.0000481 AC XY: 35AN XY: 727242
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GnomAD4 genome AF: 0.000283 AC: 43AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.000323 AC XY: 24AN XY: 74364
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 27, 2022 | The c.2433C>G (p.H811Q) alteration is located in exon 8 (coding exon 7) of the PRICKLE2 gene. This alteration results from a C to G substitution at nucleotide position 2433, causing the histidine (H) at amino acid position 811 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 21, 2021 | - - |
Progressive myoclonic epilepsy type 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 811 of the PRICKLE2 protein (p.His811Gln). This variant is present in population databases (rs113542442, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PRICKLE2-related conditions. ClinVar contains an entry for this variant (Variation ID: 578987). 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 PRICKLE2 protein function with a negative predictive value of 80%. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
REVEL
Uncertain
Polyphen
D;D;.
MutPred
Gain of relative solvent accessibility (P = 0.0999);Gain of relative solvent accessibility (P = 0.0999);.;
MVP
0.81
MPC
0.55
ClinPred
T
GERP RS
Varity_R
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at