5-146656125-T-G

Variant names:

• chr5-146656125-T-G
• rs424849
• NM_181675.4:c.448-5401A>C

Variant summary

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

The NM_181675.4(PPP2R2B):​c.448-5401A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.761 in 152,104 control chromosomes in the GnomAD database, including 45,376 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 0.76 (45376 hom., cov: 32)
• Consequence: PPP2R2B NM_181675.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0190
• Publications: 0 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.854 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R2B	NM_181675.4	MANE Select	c.448-5401A>C		intron	N/A	NP_858061.3
	PPP2R2B	NM_181674.3		c.646-5401A>C		intron	N/A	NP_858060.2
	PPP2R2B	NM_001271900.2		c.622-5401A>C		intron	N/A	NP_001258829.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R2B	ENST00000394411.9	TSL:2 MANE Select	c.448-5401A>C		intron	N/A	ENSP00000377933.3
	PPP2R2B	ENST00000394414.5	TSL:1	c.646-5401A>C		intron	N/A	ENSP00000377936.1
	PPP2R2B	ENST00000394409.7	TSL:1	c.448-5401A>C		intron	N/A	ENSP00000377931.4

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115763 AN: 151986 Hom.: 45363 Cov.: 32

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.712

Gnomad AMR AF: 0.781

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.903

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.859

Gnomad OTH AF: 0.758

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

GnomAD4 genome AF: 0.761 AC: 115819 AN: 152104 Hom.: 45376 Cov.: 32 AF XY: 0.763 AC XY: 56787 AN XY: 74382

African (AFR) AF: 0.576 AC: 23887 AN: 41438

American (AMR) AF: 0.781 AC: 11944 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 2754 AN: 3470

East Asian (EAS) AF: 0.613 AC: 3157 AN: 5152

South Asian (SAS) AF: 0.748 AC: 3606 AN: 4822

European-Finnish (FIN) AF: 0.903 AC: 9585 AN: 10618

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.859 AC: 58436 AN: 67998

Other (OTH) AF: 0.753 AC: 1590 AN: 2112

Alfa AF: 0.817 Hom.: 6393

Bravo AF: 0.744

Asia WGS AF: 0.643 AC: 2240 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.50
PhyloP100		-0.019
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: rs424849; hg19: chr5-146035688; COSMIC: COSV60758494; COSMIC: COSV60758494;