5-146878727-AGCTGCTGCTGCTGCTGCTGCTGCT-AGCTGCTGCTGCT

Variant names:

• chr5-146878727-AGCTGCTGCTGCT-A
• rs10591869
• NM_181675.4:c.-273_-262delAGCAGCAGCAGC

Variant summary

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

The NM_181675.4(PPP2R2B):​c.-273_-262delAGCAGCAGCAGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,297,600 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00012 (1 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 64 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.-273_-262delAGCAGCAGCAGC		5_prime_UTR	Exon 1 of 10	NP_858061.3	Q00005-1
	PPP2R2B	NM_001428277.1		c.-668_-657delAGCAGCAGCAGC		5_prime_UTR	Exon 1 of 9	NP_001415206.1	Q00005-1
	PPP2R2B	NM_001428279.1		c.-163_-152delAGCAGCAGCAGC		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.-273_-262delAGCAGCAGCAGC		5_prime_UTR	Exon 1 of 10	ENSP00000377933.3	Q00005-1
	PPP2R2B	ENST00000453001.5	TSL:1	c.-786_-775delAGCAGCAGCAGC		5_prime_UTR	Exon 1 of 10	ENSP00000398779.2	Q00005-6
	PPP2R2B	ENST00000394414.5	TSL:1	c.75-544_75-533delAGCAGCAGCAGC		intron	N/A	ENSP00000377936.1	Q00005-5

Frequencies

GnomAD3 genomes AF: 0.000425 AC: 64 AN: 150488 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000856

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000726

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000610

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000222

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 135 AN: 1146994 Hom.: 1 AF XY: 0.0000996 AC XY: 56 AN XY: 562104

African (AFR) AF: 0.00102 AC: 24 AN: 23470

American (AMR) AF: 0.00 AC: 0 AN: 27150

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

East Asian (EAS) AF: 0.000168 AC: 4 AN: 23798

South Asian (SAS) AF: 0.0000689 AC: 5 AN: 72538

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

Middle Eastern (MID) AF: 0.000351 AC: 1 AN: 2848

European-Non Finnish (NFE) AF: 0.000101 AC: 93 AN: 923472

Other (OTH) AF: 0.000186 AC: 8 AN: 42910

GnomAD4 genome AF: 0.000425 AC: 64 AN: 150606 Hom.: 0 Cov.: 0 AF XY: 0.000436 AC XY: 32 AN XY: 73474

African (AFR) AF: 0.000854 AC: 35 AN: 41004

American (AMR) AF: 0.000725 AC: 11 AN: 15176

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

East Asian (EAS) AF: 0.000611 AC: 3 AN: 4910

South Asian (SAS) AF: 0.00 AC: 0 AN: 4700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000222 AC: 15 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		=276/24	polymorphism

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;