5-146878727-AGCTGCTGCTGCTGCTGCTGCTGCT-AGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_181675.4(PPP2R2B):​c.-273_-262dupAGCAGCAGCAGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.095 (862 hom., cov: 0)
  • Exomes 𝑓: 0.081 (2938 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP2R2B NM_181675.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 5-146878727-A-AGCTGCTGCTGCT is Benign according to our data. Variant chr5-146878727-A-AGCTGCTGCTGCT is described in ClinVar as Benign. ClinVar VariationId is 3910485.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 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.-273_-262dupAGCAGCAGCAGC		5_prime_UTR	Exon 1 of 10	NP_858061.3	Q00005-1
	PPP2R2B	NM_001428277.1		c.-668_-657dupAGCAGCAGCAGC		5_prime_UTR	Exon 1 of 9	NP_001415206.1	Q00005-1
	PPP2R2B	NM_001428279.1		c.-163_-152dupAGCAGCAGCAGC		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_-262dupAGCAGCAGCAGC		5_prime_UTR	Exon 1 of 10	ENSP00000377933.3	Q00005-1
	PPP2R2B	ENST00000453001.5	TSL:1	c.-786_-775dupAGCAGCAGCAGC		5_prime_UTR	Exon 1 of 10	ENSP00000398779.2	Q00005-6
	PPP2R2B	ENST00000394414.5	TSL:1	c.75-544_75-533dupAGCAGCAGCAGC		intron	N/A	ENSP00000377936.1	Q00005-5

Frequencies

GnomAD3 genomes AF: 0.0947 AC: 14251 AN: 150420 Hom.: 864 Cov.: 0

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.0344

Gnomad AMR AF: 0.0751

Gnomad ASJ AF: 0.0980

Gnomad EAS AF: 0.0581

Gnomad SAS AF: 0.0810

Gnomad FIN AF: 0.0491

Gnomad MID AF: 0.103

Gnomad NFE AF: 0.0754

Gnomad OTH AF: 0.0790

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0814 AC: 92384 AN: 1134862 Hom.: 2938 Cov.: 27 AF XY: 0.0816 AC XY: 45346 AN XY: 555830

African (AFR) AF: 0.180 AC: 4185 AN: 23266

American (AMR) AF: 0.0608 AC: 1636 AN: 26926

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 1731 AN: 15000

East Asian (EAS) AF: 0.0415 AC: 977 AN: 23544

South Asian (SAS) AF: 0.0940 AC: 6722 AN: 71538

European-Finnish (FIN) AF: 0.0729 AC: 1121 AN: 15372

Middle Eastern (MID) AF: 0.0994 AC: 278 AN: 2796

European-Non Finnish (NFE) AF: 0.0788 AC: 72068 AN: 914020

Other (OTH) AF: 0.0865 AC: 3666 AN: 42400

GnomAD4 genome AF: 0.0948 AC: 14273 AN: 150538 Hom.: 862 Cov.: 0 AF XY: 0.0933 AC XY: 6852 AN XY: 73444

African (AFR) AF: 0.154 AC: 6296 AN: 40972

American (AMR) AF: 0.0750 AC: 1138 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.0980 AC: 339 AN: 3460

East Asian (EAS) AF: 0.0582 AC: 286 AN: 4910

South Asian (SAS) AF: 0.0813 AC: 382 AN: 4698

European-Finnish (FIN) AF: 0.0491 AC: 513 AN: 10438

Middle Eastern (MID) AF: 0.0966 AC: 28 AN: 290

European-Non Finnish (NFE) AF: 0.0754 AC: 5097 AN: 67612

Other (OTH) AF: 0.0781 AC: 163 AN: 2086

Alfa AF: 0.0439 Hom.: 47

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

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;