5-146878727-AGCTGCTGCTGCTGCTGCTGCTGCT-AGCTGCTGCTGCTGCTGCT

Variant names:

• chr5-146878727-AGCTGCT-A
• rs10591869
• NM_181675.4:c.-267_-262delAGCAGC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_181675.4(PPP2R2B):​c.-267_-262delAGCAGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000966 in 1,297,202 control chromosomes in the GnomAD database, including 10 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0051 (8 hom., cov: 0)
  • Exomes 𝑓: 0.00043 (2 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00507 (763/150598) while in subpopulation AFR AF = 0.0171 (701/40998). AF 95% confidence interval is 0.016. There are 8 homozygotes in GnomAd4. There are 358 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 763 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.-267_-262delAGCAGC		5_prime_UTR	Exon 1 of 10	NP_858061.3	Q00005-1
	PPP2R2B	NM_001428277.1		c.-662_-657delAGCAGC		5_prime_UTR	Exon 1 of 9	NP_001415206.1	Q00005-1
	PPP2R2B	NM_001428279.1		c.-157_-152delAGCAGC		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.-267_-262delAGCAGC		5_prime_UTR	Exon 1 of 10	ENSP00000377933.3	Q00005-1
	PPP2R2B	ENST00000453001.5	TSL:1	c.-780_-775delAGCAGC		5_prime_UTR	Exon 1 of 10	ENSP00000398779.2	Q00005-6
	PPP2R2B	ENST00000394414.5	TSL:1	c.75-538_75-533delAGCAGC		intron	N/A	ENSP00000377936.1	Q00005-5

Frequencies

GnomAD3 genomes AF: 0.00506 AC: 762 AN: 150480 Hom.: 8 Cov.: 0

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00211

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.000425

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000237

Gnomad OTH AF: 0.00532

GnomAD4 exome AF: 0.000427 AC: 490 AN: 1146604 Hom.: 2 AF XY: 0.000399 AC XY: 224 AN XY: 561906

African (AFR) AF: 0.0112 AC: 260 AN: 23316

American (AMR) AF: 0.000221 AC: 6 AN: 27132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15240

East Asian (EAS) AF: 0.0000420 AC: 1 AN: 23798

South Asian (SAS) AF: 0.000110 AC: 8 AN: 72520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15558

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

European-Non Finnish (NFE) AF: 0.000200 AC: 185 AN: 923290

Other (OTH) AF: 0.000699 AC: 30 AN: 42902

GnomAD4 genome AF: 0.00507 AC: 763 AN: 150598 Hom.: 8 Cov.: 0 AF XY: 0.00487 AC XY: 358 AN XY: 73470

African (AFR) AF: 0.0171 AC: 701 AN: 40998

American (AMR) AF: 0.00211 AC: 32 AN: 15176

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

East Asian (EAS) AF: 0.000204 AC: 1 AN: 4910

South Asian (SAS) AF: 0.000426 AC: 2 AN: 4698

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: 0.000237 AC: 16 AN: 67634

Other (OTH) AF: 0.00527 AC: 11 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		=299/1	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;