5-146878727-AGCTGCTGCTGCTGCTGCTGCTGCT-AGCTGCTGCTGCTGCTGCTGCT

Position:

• chr5-146878727-AGCTGCTGCTGCTGCTGCTGCTGCT-AGCTGCTGCTGCTGCTGCTGCT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_181675.4(PPP2R2B):​c.-264_-262del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0304 in 1,278,638 control chromosomes in the GnomAD database, including 1,618 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.076 (1019 hom., cov: 0)
  • Exomes 𝑓: 0.024 (599 hom.)
• Consequence: PPP2R2B NM_181675.4 5_prime_UTR
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.19

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 5-146878727-AGCT-A is Benign according to our data. Variant chr5-146878727-AGCT-A is described in ClinVar as [Benign]. Clinvar id is 3056407.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-146878727-AGCT-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R2B	NM_181675.4	c.-264_-262del		5_prime_UTR_variant	1/10	ENST00000394411.9	NP_858061.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R2B	ENST00000394411.9	c.-264_-262del		5_prime_UTR_variant	1/10	2	NM_181675.4	ENSP00000377933	P3

Frequencies

GnomAD3 genomes AF: 0.0758 AC: 11406 AN: 150414 Hom.: 1015 Cov.: 0

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.0100

Gnomad AMR AF: 0.0363

Gnomad ASJ AF: 0.0454

Gnomad EAS AF: 0.0226

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.00575

Gnomad MID AF: 0.0353

Gnomad NFE AF: 0.0237

Gnomad OTH AF: 0.0770

GnomAD4 exome AF: 0.0243 AC: 27398 AN: 1128108 Hom.: 599 AF XY: 0.0231 AC XY: 12775 AN XY: 552356

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.00923

Gnomad4 ASJ exome AF: 0.0232

Gnomad4 EAS exome AF: 0.00447

Gnomad4 SAS exome AF: 0.00952

Gnomad4 FIN exome AF: 0.00856

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0281

GnomAD4 genome AF: 0.0759 AC: 11427 AN: 150530 Hom.: 1019 Cov.: 0 AF XY: 0.0736 AC XY: 5403 AN XY: 73430

Gnomad4 AFR AF: 0.213

Gnomad4 AMR AF: 0.0361

Gnomad4 ASJ AF: 0.0454

Gnomad4 EAS AF: 0.0226

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.00575

Gnomad4 NFE AF: 0.0237

Gnomad4 OTH AF: 0.0761

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PPP2R2B-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10591869; hg19: chr5-146258290;