5-146878727-AGCTGCTGCTGCTGCTGCTGCTGCT-AGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant names:

• chr5-146878727-A-AGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT
• rs10591869
• ENST00000530902.5:n.167_168insAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC

Variant summary

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

The ENST00000530902.5(PPP2R2B):​n.167_168insAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC variant causes a non coding transcript exon 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00067 (37 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP2R2B ENST00000530902.5 non_coding_transcript_exon
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 172 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R2B	NM_181675.4	c.-262_-261insAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC		5_prime_UTR_variant	Exon 1 of 10	ENST00000394411.9	NP_858061.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R2B	ENST00000394411.9	c.-262_-261insAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC		5_prime_UTR_variant	Exon 1 of 10	2	NM_181675.4	ENSP00000377933.3

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 172 AN: 150486 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000709

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00396

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.000610

Gnomad SAS AF: 0.00340

Gnomad FIN AF: 0.000766

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000739

Gnomad OTH AF: 0.000484

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000669 AC: 767 AN: 1146968 Hom.: 37 Cov.: 27 AF XY: 0.000822 AC XY: 462 AN XY: 562092

African (AFR) AF: 0.000639 AC: 15 AN: 23466

American (AMR) AF: 0.00125 AC: 34 AN: 27150

Ashkenazi Jewish (ASJ) AF: 0.00249 AC: 38 AN: 15244

East Asian (EAS) AF: 0.00429 AC: 102 AN: 23786

South Asian (SAS) AF: 0.00283 AC: 205 AN: 72534

European-Finnish (FIN) AF: 0.00193 AC: 30 AN: 15562

Middle Eastern (MID) AF: 0.000702 AC: 2 AN: 2848

European-Non Finnish (NFE) AF: 0.000322 AC: 297 AN: 923464

Other (OTH) AF: 0.00103 AC: 44 AN: 42914

GnomAD4 genome AF: 0.00114 AC: 172 AN: 150604 Hom.: 1 Cov.: 0 AF XY: 0.00137 AC XY: 101 AN XY: 73474

African (AFR) AF: 0.000707 AC: 29 AN: 41002

American (AMR) AF: 0.00395 AC: 60 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 5 AN: 3460

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

South Asian (SAS) AF: 0.00340 AC: 16 AN: 4700

European-Finnish (FIN) AF: 0.000766 AC: 8 AN: 10442

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

European-Non Finnish (NFE) AF: 0.000739 AC: 50 AN: 67634

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.00 Hom.: 47

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=300/0	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;