5-146874330-T-C

Variant names:

• chr5-146874330-T-C
• rs319217
• NM_181675.4:c.70+3672A>G

Variant summary

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

The NM_181675.4(PPP2R2B):​c.70+3672A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 152,136 control chromosomes in the GnomAD database, including 19,804 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 0.49 (19804 hom., cov: 33)
• Consequence: PPP2R2B NM_181675.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.436
• Publications: 12 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R2B	NM_181675.4	c.70+3672A>G		intron_variant	Intron 2 of 9	ENST00000394411.9	NP_858061.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R2B	ENST00000394411.9	c.70+3672A>G		intron_variant	Intron 2 of 9	2	NM_181675.4	ENSP00000377933.3

Frequencies

GnomAD3 genomes AF: 0.487 AC: 74035 AN: 152018 Hom.: 19775 Cov.: 33

Gnomad AFR AF: 0.693

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.483

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.488

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

GnomAD4 genome AF: 0.487 AC: 74121 AN: 152136 Hom.: 19804 Cov.: 33 AF XY: 0.487 AC XY: 36207 AN XY: 74366

African (AFR) AF: 0.693 AC: 28770 AN: 41502

American (AMR) AF: 0.483 AC: 7379 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1683 AN: 3466

East Asian (EAS) AF: 0.720 AC: 3724 AN: 5170

South Asian (SAS) AF: 0.557 AC: 2684 AN: 4820

European-Finnish (FIN) AF: 0.289 AC: 3056 AN: 10588

Middle Eastern (MID) AF: 0.462 AC: 135 AN: 292

European-Non Finnish (NFE) AF: 0.372 AC: 25291 AN: 68000

Other (OTH) AF: 0.483 AC: 1018 AN: 2106

Alfa AF: 0.313 Hom.: 869

Bravo AF: 0.511

Asia WGS AF: 0.629 AC: 2183 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.8
DANN	Benign	0.73
PhyloP100		0.44
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: rs319217; hg19: chr5-146253893; COSMIC: COSV60758967;