5-146878727-AGCTGCTGCTGCTGCTGCTGCTGCT-AGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant names:

• chr5-146878727-A-AGCTGCTGCTGCTGCT
• rs10591869
• ENST00000530902.5:n.153_167dupAGCAGCAGCAGCAGC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The ENST00000530902.5(PPP2R2B):​n.153_167dupAGCAGCAGCAGCAGC variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.097 (713 hom., cov: 0)
  • Exomes 𝑓: 0.10 (6937 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP2R2B ENST00000530902.5 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.19
• Publications: 4 publications found

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]

PPP2R2B Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 12

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 5-146878727-A-AGCTGCTGCTGCTGCT is Benign according to our data. Variant chr5-146878727-A-AGCTGCTGCTGCTGCT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218860.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R2B	NM_181675.4	c.-276_-262dupAGCAGCAGCAGCAGC		5_prime_UTR_variant	Exon 1 of 10	ENST00000394411.9	NP_858061.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R2B	ENST00000394411.9	c.-276_-262dupAGCAGCAGCAGCAGC		5_prime_UTR_variant	Exon 1 of 10	2	NM_181675.4	ENSP00000377933.3

Frequencies

GnomAD3 genomes AF: 0.0968 AC: 14559 AN: 150420 Hom.: 709 Cov.: 0

Gnomad AFR AF: 0.0771

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0788

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.0657

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0518

Gnomad MID AF: 0.103

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.0988

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.101 AC: 109718 AN: 1087864 Hom.: 6937 Cov.: 27 AF XY: 0.104 AC XY: 55423 AN XY: 534104

African (AFR) AF: 0.0771 AC: 1763 AN: 22856

American (AMR) AF: 0.0840 AC: 2229 AN: 26540

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 1979 AN: 14898

East Asian (EAS) AF: 0.0832 AC: 1848 AN: 22206

South Asian (SAS) AF: 0.115 AC: 8174 AN: 71258

European-Finnish (FIN) AF: 0.102 AC: 1574 AN: 15420

Middle Eastern (MID) AF: 0.111 AC: 303 AN: 2738

European-Non Finnish (NFE) AF: 0.100 AC: 87238 AN: 870982

Other (OTH) AF: 0.113 AC: 4610 AN: 40966

GnomAD4 genome AF: 0.0968 AC: 14569 AN: 150536 Hom.: 713 Cov.: 0 AF XY: 0.0940 AC XY: 6901 AN XY: 73432

African (AFR) AF: 0.0773 AC: 3168 AN: 40982

American (AMR) AF: 0.0789 AC: 1196 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 403 AN: 3460

East Asian (EAS) AF: 0.0656 AC: 322 AN: 4906

South Asian (SAS) AF: 0.124 AC: 583 AN: 4696

European-Finnish (FIN) AF: 0.0518 AC: 541 AN: 10440

Middle Eastern (MID) AF: 0.107 AC: 31 AN: 290

European-Non Finnish (NFE) AF: 0.119 AC: 8048 AN: 67612

Other (OTH) AF: 0.0968 AC: 202 AN: 2086

Alfa AF: 0.0467 Hom.: 47

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PPP2R2B-related disorder Benign:1

Feb 20, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10591869; hg19: chr5-146258290;