5-146869538-C-T

Variant names:

• chr5-146869538-C-T
• rs10037715
• NM_181675.4:c.70+8464G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181674.3(PPP2R2B):​c.268+8464G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 151,932 control chromosomes in the GnomAD database, including 6,882 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (6882 hom., cov: 32)
• Consequence: PPP2R2B NM_181674.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181674.3. 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.70+8464G>A		intron	N/A	NP_858061.3
	PPP2R2B	NM_181674.3		c.268+8464G>A		intron	N/A	NP_858060.2
	PPP2R2B	NM_001271900.2		c.244+8464G>A		intron	N/A	NP_001258829.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R2B	ENST00000394411.9	TSL:2 MANE Select	c.70+8464G>A		intron	N/A	ENSP00000377933.3
	PPP2R2B	ENST00000394414.5	TSL:1	c.268+8464G>A		intron	N/A	ENSP00000377936.1
	PPP2R2B	ENST00000394409.7	TSL:1	c.70+8464G>A		intron	N/A	ENSP00000377931.4

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45025 AN: 151814 Hom.: 6883 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.312

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.296 AC: 45046 AN: 151932 Hom.: 6882 Cov.: 32 AF XY: 0.291 AC XY: 21633 AN XY: 74240

African (AFR) AF: 0.254 AC: 10528 AN: 41406

American (AMR) AF: 0.315 AC: 4809 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1320 AN: 3466

East Asian (EAS) AF: 0.349 AC: 1792 AN: 5140

South Asian (SAS) AF: 0.279 AC: 1347 AN: 4822

European-Finnish (FIN) AF: 0.223 AC: 2358 AN: 10572

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21881 AN: 67938

Other (OTH) AF: 0.307 AC: 648 AN: 2112

Alfa AF: 0.317 Hom.: 12410

Bravo AF: 0.303

Asia WGS AF: 0.294 AC: 1020 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.77
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs10037715; hg19: chr5-146249101; COSMIC: COSV60758962;