rs775889804
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_198859.4(PRICKLE2):c.400G>A(p.Gly134Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
PRICKLE2
NM_198859.4 missense
NM_198859.4 missense
Scores
4
10
2
Clinical Significance
Conservation
PhyloP100: 7.57
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 -2 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.881
BS2
High AC in GnomAdExome4 at 10 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRICKLE2 | NM_198859.4 | c.400G>A | p.Gly134Arg | missense_variant | 5/8 | ENST00000638394.2 | |
PRICKLE2 | NM_001370528.1 | c.400G>A | p.Gly134Arg | missense_variant | 5/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRICKLE2 | ENST00000638394.2 | c.400G>A | p.Gly134Arg | missense_variant | 5/8 | 1 | NM_198859.4 | ||
PRICKLE2 | ENST00000295902.11 | c.568G>A | p.Gly190Arg | missense_variant | 6/9 | 5 | P1 | ||
PRICKLE2 | ENST00000564377.6 | c.400G>A | p.Gly134Arg | missense_variant | 5/8 | 5 | |||
PRICKLE2 | ENST00000640303.1 | n.1039G>A | non_coding_transcript_exon_variant | 3/6 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152250Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249140Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134964
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GnomAD4 exome AF: 0.00000685 AC: 10AN: 1460526Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9AN XY: 726616
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152250Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74384
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
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 | Aug 26, 2022 | The c.400G>A (p.G134R) alteration is located in exon 5 (coding exon 4) of the PRICKLE2 gene. This alteration results from a G to A substitution at nucleotide position 400, causing the glycine (G) at amino acid position 134 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Progressive myoclonic epilepsy type 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2017 | This variant is present in population databases (rs775889804, ExAC 0.01%). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PRICKLE2-related disease. This sequence change replaces glycine with arginine at codon 134 of the PRICKLE2 protein (p.Gly134Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
M;M;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
REVEL
Uncertain
Polyphen
P;P;.
MutPred
Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);.;
MVP
0.72
MPC
0.86
ClinPred
D
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at