5-146878727-AGCTGCTGCTGCTGCTGCTGCTGCT-AGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant names:

• chr5-146878727-A-AGCTGCTGCT
• rs10591869
• NM_181675.4:c.-270_-262dupAGCAGCAGC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_181675.4(PPP2R2B):​c.-270_-262dupAGCAGCAGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,289,898 control chromosomes in the GnomAD database, including 7,109 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (1619 hom., cov: 0)
  • Exomes 𝑓: 0.13 (5490 hom.)
• Consequence: PPP2R2B NM_181675.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181675.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R2B	NM_181675.4	MANE Select	c.-270_-262dupAGCAGCAGC		5_prime_UTR	Exon 1 of 10	NP_858061.3	Q00005-1
	PPP2R2B	NM_001428277.1		c.-665_-657dupAGCAGCAGC		5_prime_UTR	Exon 1 of 9	NP_001415206.1	Q00005-1
	PPP2R2B	NM_001428279.1		c.-160_-152dupAGCAGCAGC		5_prime_UTR	Exon 1 of 10	NP_001415208.1	Q00005-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R2B	ENST00000394411.9	TSL:2 MANE Select	c.-270_-262dupAGCAGCAGC		5_prime_UTR	Exon 1 of 10	ENSP00000377933.3	Q00005-1
	PPP2R2B	ENST00000453001.5	TSL:1	c.-783_-775dupAGCAGCAGC		5_prime_UTR	Exon 1 of 10	ENSP00000398779.2	Q00005-6
	PPP2R2B	ENST00000394414.5	TSL:1	c.75-541_75-533dupAGCAGCAGC		intron	N/A	ENSP00000377936.1	Q00005-5

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21147 AN: 150410 Hom.: 1617 Cov.: 0

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.0819

Gnomad MID AF: 0.186

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.162

GnomAD4 exome AF: 0.125 AC: 142786 AN: 1139370 Hom.: 5490 Cov.: 27 AF XY: 0.128 AC XY: 71407 AN XY: 558292

African (AFR) AF: 0.159 AC: 3632 AN: 22880

American (AMR) AF: 0.198 AC: 5342 AN: 26916

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 3424 AN: 15086

East Asian (EAS) AF: 0.157 AC: 3587 AN: 22916

South Asian (SAS) AF: 0.202 AC: 14501 AN: 71856

European-Finnish (FIN) AF: 0.0878 AC: 1352 AN: 15390

Middle Eastern (MID) AF: 0.174 AC: 489 AN: 2806

European-Non Finnish (NFE) AF: 0.114 AC: 104365 AN: 918954

Other (OTH) AF: 0.143 AC: 6094 AN: 42566

GnomAD4 genome AF: 0.141 AC: 21167 AN: 150528 Hom.: 1619 Cov.: 0 AF XY: 0.141 AC XY: 10351 AN XY: 73434

African (AFR) AF: 0.152 AC: 6207 AN: 40966

American (AMR) AF: 0.165 AC: 2504 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 735 AN: 3460

East Asian (EAS) AF: 0.277 AC: 1359 AN: 4902

South Asian (SAS) AF: 0.200 AC: 940 AN: 4700

European-Finnish (FIN) AF: 0.0819 AC: 855 AN: 10436

Middle Eastern (MID) AF: 0.186 AC: 54 AN: 290

European-Non Finnish (NFE) AF: 0.117 AC: 7941 AN: 67614

Other (OTH) AF: 0.162 AC: 338 AN: 2088

Alfa AF: 0.0634 Hom.: 47

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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;