5-146878727-AGCTGCTGCTGCTGCTGCTGCTGCT-AGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant names:

• chr5-146878727-A-AGCTGCTGCTGCTGCTGCT
• rs10591869
• ENST00000530902.5:n.150_167dupAGCAGCAGCAGCAGCAGC

Variant summary

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

The ENST00000530902.5(PPP2R2B):​n.150_167dupAGCAGCAGCAGCAGCAGC 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 Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.029 (193 hom., cov: 0)
  • Exomes 𝑓: 0.022 (2642 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP2R2B ENST00000530902.5 non_coding_transcript_exon
• Clinical Significance: Benign no assertion criteria provided B:1
• 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-AGCTGCTGCTGCTGCTGCT is Benign according to our data. Variant chr5-146878727-A-AGCTGCTGCTGCTGCTGCT is described in ClinVar as [Benign]. Clinvar id is 3059028.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R2B	NM_181675.4	c.-279_-262dupAGCAGCAGCAGCAGCAGC		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.-279_-262dupAGCAGCAGCAGCAGCAGC		5_prime_UTR_variant	Exon 1 of 10	2	NM_181675.4	ENSP00000377933.3

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 4312 AN: 150468 Hom.: 192 Cov.: 0

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0932

Gnomad ASJ AF: 0.00318

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.0198

Gnomad FIN AF: 0.0326

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.0281

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0222 AC: 25400 AN: 1143696 Hom.: 2642 Cov.: 27 AF XY: 0.0224 AC XY: 12562 AN XY: 560538

African (AFR) AF: 0.0233 AC: 545 AN: 23360

American (AMR) AF: 0.164 AC: 4422 AN: 27038

Ashkenazi Jewish (ASJ) AF: 0.00834 AC: 127 AN: 15234

East Asian (EAS) AF: 0.300 AC: 6948 AN: 23172

South Asian (SAS) AF: 0.0252 AC: 1824 AN: 72298

European-Finnish (FIN) AF: 0.0593 AC: 920 AN: 15514

Middle Eastern (MID) AF: 0.0159 AC: 45 AN: 2830

European-Non Finnish (NFE) AF: 0.0101 AC: 9296 AN: 921492

Other (OTH) AF: 0.0298 AC: 1273 AN: 42758

GnomAD4 genome AF: 0.0287 AC: 4326 AN: 150586 Hom.: 193 Cov.: 0 AF XY: 0.0316 AC XY: 2323 AN XY: 73466

African (AFR) AF: 0.0207 AC: 850 AN: 41002

American (AMR) AF: 0.0937 AC: 1421 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.00318 AC: 11 AN: 3460

East Asian (EAS) AF: 0.168 AC: 825 AN: 4906

South Asian (SAS) AF: 0.0204 AC: 96 AN: 4696

European-Finnish (FIN) AF: 0.0326 AC: 340 AN: 10442

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.0107 AC: 722 AN: 67632

Other (OTH) AF: 0.0278 AC: 58 AN: 2088

Alfa AF: 0.0143 Hom.: 47

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PPP2R2B-related disorder Benign:1

Feb 04, 2022

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;