5-146638334-T-C

Position:

• chr5-146638334-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_181675.4(PPP2R2B):​c.707A>G​(p.Asn236Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000242 in 1,613,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: PPP2R2B NM_181675.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PPP2R2B. . Gene score misZ 2.2458 (greater than the threshold 3.09). Trascript score misZ 3.5161 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia type 12.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12239623).
• BS2: High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP2R2B	NM_181675.4	c.707A>G	p.Asn236Ser	missense_variant	7/10	ENST00000394411.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP2R2B	ENST00000394411.9	c.707A>G	p.Asn236Ser	missense_variant	7/10	2	NM_181675.4	P3

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000295 AC: 74 AN: 251218 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000246 AC: 360 AN: 1461474 Hom.: 0 Cov.: 31 AF XY: 0.000234 AC XY: 170 AN XY: 727050

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152166 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74342

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000299 Hom.: 0

Bravo AF: 0.000174

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000327

EpiControl AF: 0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;.;.;D;.;.;.;.
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D;D;D;D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;.;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.1	.;D;D;D;.;D;D;.
REVEL	Benign	0.074
Sift	Benign	0.082	.;T;T;T;.;T;T;.
Sift4G	Benign	0.21	T;T;T;T;T;T;T;T
Polyphen		0.044	B;.;B;B;.;B;B;B
Vest4		0.35
MVP		0.67
MPC		0.55
ClinPred		0.13	T
GERP RS		5.2
Varity_R		0.23
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs150981315; hg19: chr5-146017897;