5-146878727-AGCTGCTGCTGCTGCTGCTGCTGCT-AGCTGCTGCTGCTGCT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_181675.4(PPP2R2B):​c.-270_-262delAGCAGCAGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,297,592 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00019 (0 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 77 AD gene.

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_-262delAGCAGCAGC		5_prime_UTR	Exon 1 of 10	NP_858061.3	Q00005-1
	PPP2R2B	NM_001428277.1		c.-665_-657delAGCAGCAGC		5_prime_UTR	Exon 1 of 9	NP_001415206.1	Q00005-1
	PPP2R2B	NM_001428279.1		c.-160_-152delAGCAGCAGC		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_-262delAGCAGCAGC		5_prime_UTR	Exon 1 of 10	ENSP00000377933.3	Q00005-1
	PPP2R2B	ENST00000453001.5	TSL:1	c.-783_-775delAGCAGCAGC		5_prime_UTR	Exon 1 of 10	ENSP00000398779.2	Q00005-6
	PPP2R2B	ENST00000394414.5	TSL:1	c.75-541_75-533delAGCAGCAGC		intron	N/A	ENSP00000377936.1	Q00005-5

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 77 AN: 150488 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000858

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000406

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.0000958

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000192 AC: 220 AN: 1146986 Hom.: 0 AF XY: 0.000180 AC XY: 101 AN XY: 562104

African (AFR) AF: 0.000682 AC: 16 AN: 23468

American (AMR) AF: 0.0000368 AC: 1 AN: 27150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15244

East Asian (EAS) AF: 0.000294 AC: 7 AN: 23798

South Asian (SAS) AF: 0.0000827 AC: 6 AN: 72536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2848

European-Non Finnish (NFE) AF: 0.000198 AC: 183 AN: 923464

Other (OTH) AF: 0.000163 AC: 7 AN: 42914

GnomAD4 genome AF: 0.000511 AC: 77 AN: 150606 Hom.: 0 Cov.: 0 AF XY: 0.000504 AC XY: 37 AN XY: 73474

African (AFR) AF: 0.00110 AC: 45 AN: 41004

American (AMR) AF: 0.000857 AC: 13 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.000407 AC: 2 AN: 4910

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4700

European-Finnish (FIN) AF: 0.0000958 AC: 1 AN: 10442

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000207 AC: 14 AN: 67634

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 47

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=288/12	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10591869; hg19: chr5-146258290;