chr5-146650601-C-A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6_ModerateBS2
The NM_181675.4(PPP2R2B):c.571G>T(p.Ala191Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,613,928 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 Likely benign (★).
Frequency
Genomes: 𝑓 0.00099 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000085 ( 0 hom. )
Consequence
PPP2R2B
NM_181675.4 missense
NM_181675.4 missense
Scores
1
5
10
Clinical Significance
Conservation
PhyloP100: 3.26
Genes affected
PPP2R2B (HGNC:9305): (protein phosphatase 2 regulatory subunit Bbeta) The product of this gene belongs to the phosphatase 2 regulatory subunit B family. Protein phosphatase 2 is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. The B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a beta isoform of the regulatory subunit B55 subfamily. Defects in this gene cause autosomal dominant spinocerebellar ataxia 12 (SCA12), a disease caused by degeneration of the cerebellum, sometimes involving the brainstem and spinal cord, and in resulting in poor coordination of speech and body movements. Multiple alternatively spliced variants, which encode different isoforms, have been identified for this gene. The 5' UTR of some of these variants includes a CAG trinucleotide repeat sequence (7-28 copies) that can be expanded to 55-78 copies in cases of SCA12. [provided by RefSeq, Jul 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, PPP2R2B
BP4
?
Computational evidence support a benign effect (MetaRNN=0.017226875).
BP6
?
Variant 5-146650601-C-A is Benign according to our data. Variant chr5-146650601-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1049044.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
?
High AC in GnomAd at 150 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PPP2R2B | NM_181675.4 | c.571G>T | p.Ala191Ser | missense_variant | 6/10 | ENST00000394411.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PPP2R2B | ENST00000394411.9 | c.571G>T | p.Ala191Ser | missense_variant | 6/10 | 2 | NM_181675.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000986 AC: 150AN: 152150Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000251 AC: 63AN: 250960Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135652
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GnomAD4 exome AF: 0.0000848 AC: 124AN: 1461660Hom.: 0 Cov.: 31 AF XY: 0.0000743 AC XY: 54AN XY: 727130
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PPP2R2B p.Ala180Ser variant was not identified in the literature or in the ClinVar, Cosmic or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs143485788) and in control databases in 92 of 282368 chromosomes at a frequency of 0.000326 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 87 of 24954 chromosomes (freq: 0.003486), Latino in 2 of 35398 chromosomes (freq: 0.000057), South Asian in 1 of 30594 chromosomes (freq: 0.000033), European (non-Finnish) in 1 of 128888 chromosomes (freq: 0.000008), and Other in 1 of 7200 chromosomes (freq: 0.000139); it was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The p.Ala180 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
PPP2R2B-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 06, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.;.;T;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.;M;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
T
REVEL
Benign
Sift4G
Benign
T;T;T;T;T;T;T;T
Polyphen
B;.;B;B;.;B;B;B
Vest4
MVP
MPC
1.3
ClinPred
T
GERP RS
Varity_R
gMVP
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