5-146697963-C-T

Variant names:

• chr5-146697963-C-T
• rs6879694
• NM_181675.4:c.334+16G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_181675.4(PPP2R2B):​c.334+16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,597,466 control chromosomes in the GnomAD database, including 21,557 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (2511 hom., cov: 31)
  • Exomes 𝑓: 0.16 (19046 hom.)
• Consequence: PPP2R2B NM_181675.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.42
• Publications: 10 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 5-146697963-C-T is Benign according to our data. Variant chr5-146697963-C-T is described in ClinVar as Benign. ClinVar VariationId is 1272737.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.253 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.334+16G>A		intron	N/A	NP_858061.3
	PPP2R2B	NM_181674.3		c.532+16G>A		intron	N/A	NP_858060.2
	PPP2R2B	NM_001271900.2		c.508+16G>A		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.334+16G>A		intron	N/A	ENSP00000377933.3
	PPP2R2B	ENST00000394414.5	TSL:1	c.532+16G>A		intron	N/A	ENSP00000377936.1
	PPP2R2B	ENST00000394409.7	TSL:1	c.334+16G>A		intron	N/A	ENSP00000377931.4

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26754 AN: 151780 Hom.: 2510 Cov.: 31

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.0954

Gnomad EAS AF: 0.264

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.160

GnomAD2 exomes AF: 0.169 AC: 40081 AN: 236964 AF XY: 0.165

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.239

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.158 AC: 228982 AN: 1445568 Hom.: 19046 Cov.: 30 AF XY: 0.158 AC XY: 113283 AN XY: 718994

African (AFR) AF: 0.249 AC: 8055 AN: 32374

American (AMR) AF: 0.198 AC: 8373 AN: 42218

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2541 AN: 25122

East Asian (EAS) AF: 0.274 AC: 10773 AN: 39386

South Asian (SAS) AF: 0.157 AC: 13140 AN: 83660

European-Finnish (FIN) AF: 0.139 AC: 7350 AN: 52806

Middle Eastern (MID) AF: 0.150 AC: 849 AN: 5664

European-Non Finnish (NFE) AF: 0.153 AC: 168589 AN: 1104736

Other (OTH) AF: 0.156 AC: 9312 AN: 59602

GnomAD4 genome AF: 0.176 AC: 26767 AN: 151898 Hom.: 2511 Cov.: 31 AF XY: 0.176 AC XY: 13029 AN XY: 74220

African (AFR) AF: 0.237 AC: 9803 AN: 41404

American (AMR) AF: 0.165 AC: 2510 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0954 AC: 331 AN: 3470

East Asian (EAS) AF: 0.264 AC: 1363 AN: 5154

South Asian (SAS) AF: 0.165 AC: 795 AN: 4804

European-Finnish (FIN) AF: 0.139 AC: 1466 AN: 10540

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 9997 AN: 67956

Other (OTH) AF: 0.165 AC: 349 AN: 2110

Alfa AF: 0.152 Hom.: 4669

Bravo AF: 0.186

Asia WGS AF: 0.216 AC: 750 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.069
DANN	Benign	0.31
PhyloP100		-2.4
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: rs6879694; hg19: chr5-146077526; COSMIC: COSV60765670; COSMIC: COSV60765670;