NM_153026.3:c.2216C>T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_153026.3(PRICKLE1):c.2216C>T(p.Ser739Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00107 in 1,614,136 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_153026.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRICKLE1 | NM_153026.3 | c.2216C>T | p.Ser739Phe | missense_variant | Exon 8 of 8 | ENST00000345127.9 | NP_694571.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000605 AC: 92AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000772 AC: 194AN: 251266Hom.: 0 AF XY: 0.000677 AC XY: 92AN XY: 135804
GnomAD4 exome AF: 0.00112 AC: 1630AN: 1461878Hom.: 0 Cov.: 34 AF XY: 0.00107 AC XY: 781AN XY: 727240
GnomAD4 genome AF: 0.000604 AC: 92AN: 152258Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41AN XY: 74434
ClinVar
Submissions by phenotype
not provided Uncertain:4
- -
A variant of uncertain significance has been identified in the PRICKLE1 gene. The S739F variant in the PRICKLE1 gene was previously identified in a patient with myelomeningocele and was not detected in controls so it was suggested to contribute to an increased risk for open neural tube defects; however, the variant was inherited from the patient's unaffected mother and did not co-segregate with neural tube defects in the extended family (Bosoi et al., 2011). The S739F variant is observed in 181/126496 (0.14%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. However, the S739F 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
- -
- -
Epilepsy, progressive myoclonic, 1B Uncertain:2
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 739 of the PRICKLE1 protein (p.Ser739Phe). This variant is present in population databases (rs138452760, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with myelomeningocele (PMID: 21901791). ClinVar contains an entry for this variant (Variation ID: 198918). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -
- -
Self-limited epilepsy with centrotemporal spikes Pathogenic:1
CAADphred>15 -
Intellectual disability Uncertain:1
- -
not specified Benign:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at