rs1131691266
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_006245.4(PPP2R5D):c.758G>A(p.Arg253Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,882 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R253G) has been classified as Pathogenic.
Frequency
Consequence
NM_006245.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PPP2R5D | NM_006245.4 | c.758G>A | p.Arg253Gln | missense_variant | 7/16 | ENST00000485511.6 | |
PPP2R5D | NM_180976.3 | c.662G>A | p.Arg221Gln | missense_variant | 7/16 | ||
PPP2R5D | NM_180977.3 | c.440G>A | p.Arg147Gln | missense_variant | 5/14 | ||
PPP2R5D | NM_001270476.2 | c.305G>A | p.Arg102Gln | missense_variant | 7/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PPP2R5D | ENST00000485511.6 | c.758G>A | p.Arg253Gln | missense_variant | 7/16 | 1 | NM_006245.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251494Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135922
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461882Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727242
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hogue-Janssens syndrome 1 Pathogenic:1Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing;provider interpretation | Geisinger Autism and Developmental Medicine Institute, Geisinger Health System | Oct 31, 2017 | This 5 year old male has a history of global developmental delay, macrocephaly, hypotonia, vision abnormalities, torticollis, and plagiocephaly. This variant is absent from gnomAD but present in ExAC at a frequency of 0.0008121% overall. Computational models suggest that this variant is probably damaging to protein structure and/or function. The variant was inherited from the patient's father who has a history of dyslexia and who required learning supports in elementary school. Pathogenic de novo missense variants in PPP2R5D have been reported in individuals with intellectual disability, autism spectrum disorder, macrocephaly, hypotonia, increased height, seizures, and dysmorphic features (PMID:25972378; PMID:26576547). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | A Heterozygous Missense variant c.758G>A in Exon 7 of the PPP2R5D gene that results in the amino acid substitution p.Arg253Gln was identified. The observed variant has a minor allele frequency of 0.00001% in gnomAD exomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Likely Pathogenic and Uncertain Significance (variant ID: 429222). This variant has previously been reported for neurodevelopmental disorders (Krgovic D et al., 2022). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. - |
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 09, 2023 | Reported heterozygous in a patient with autism and intellectual disability in published literature without additional clinical information or familial segregation information (Krgovic et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35813072, 37167322, 36833222) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 12, 2022 | 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 missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 429222). This variant has not been reported in the literature in individuals affected with PPP2R5D-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 253 of the PPP2R5D protein (p.Arg253Gln). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at