5-146878727-AGCTGCTGCTGCTGCTGCTGCTGCT-AGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Position:

• chr5-146878727-AGCTGCTGCTGCTGCTGCTGCTGCT-AGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_181675.4(PPP2R2B):​c.-262_-261insAGCAGCAGCAGCAGCAGCAGCAGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (31 hom., cov: 0)
  • Exomes 𝑓: 0.017 (1024 hom.)
  • Failed GnomAD Quality Control
• 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-A-AGCTGCTGCTGCTGCTGCTGCTGCT is Benign according to our data. Variant chr5-146878727-A-AGCTGCTGCTGCTGCTGCTGCTGCT is described in ClinVar as [Benign]. Clinvar id is 3037533.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0148 (2225/150590) while in subpopulation EAS AF= 0.0407 (200/4910). AF 95% confidence interval is 0.0361. There are 31 homozygotes in gnomad4. There are 1106 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2225 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R2B	NM_181675.4	c.-262_-261insAGCAGCAGCAGCAGCAGCAGCAGC		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.-262_-261insAGCAGCAGCAGCAGCAGCAGCAGC		5_prime_UTR_variant	1/10	2	NM_181675.4	ENSP00000377933	P3

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2223 AN: 150472 Hom.: 31 Cov.: 0

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.0244

Gnomad AMR AF: 0.00666

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0410

Gnomad SAS AF: 0.0387

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.0106

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0170 AC: 19423 AN: 1143590 Hom.: 1024 Cov.: 27 AF XY: 0.0180 AC XY: 10075 AN XY: 560504

Gnomad4 AFR exome AF: 0.0298

Gnomad4 AMR exome AF: 0.00800

Gnomad4 ASJ exome AF: 0.00112

Gnomad4 EAS exome AF: 0.0705

Gnomad4 SAS exome AF: 0.0396

Gnomad4 FIN exome AF: 0.0340

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.0190

GnomAD4 genome AF: 0.0148 AC: 2225 AN: 150590 Hom.: 31 Cov.: 0 AF XY: 0.0151 AC XY: 1106 AN XY: 73470

Gnomad4 AFR AF: 0.0178

Gnomad4 AMR AF: 0.00666

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0407

Gnomad4 SAS AF: 0.0387

Gnomad4 FIN AF: 0.0144

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.0105

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

Feb 25, 2020

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;