5-146600310-C-A

Variant names:

• chr5-146600310-C-A
• rs140308315
• NM_181675.4:c.941G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_181675.4(PPP2R2B):​c.941G>T​(p.Arg314Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R314C) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PPP2R2B NM_181675.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.39
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000250407 (HGNC:58421):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41619158).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R2B	NM_181675.4	MANE Select	c.941G>T	p.Arg314Leu	missense	Exon 8 of 10	NP_858061.3	Q00005-1
	PPP2R2B	NM_181674.3		c.1139G>T	p.Arg380Leu	missense	Exon 8 of 10	NP_858060.2	Q00005-5
	PPP2R2B	NM_001271900.2		c.1115G>T	p.Arg372Leu	missense	Exon 9 of 11	NP_001258829.1	Q00005-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R2B	ENST00000394411.9	TSL:2 MANE Select	c.941G>T	p.Arg314Leu	missense	Exon 8 of 10	ENSP00000377933.3	Q00005-1
	PPP2R2B	ENST00000394414.5	TSL:1	c.1139G>T	p.Arg380Leu	missense	Exon 8 of 10	ENSP00000377936.1	Q00005-5
	PPP2R2B	ENST00000394409.7	TSL:1	c.941G>T	p.Arg314Leu	missense	Exon 7 of 9	ENSP00000377931.4	Q00005-1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41530

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2114

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	0.017
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.17
Sift	Benign	0.073	T
Sift4G	Benign	0.10	T
Polyphen		0.0010	B
Vest4		0.54
MutPred		0.43		Loss of helix (P = 0.0304)
MVP		0.43
MPC		0.81
ClinPred		0.99	D
GERP RS		4.6
PromoterAI		-0.016	Neutral
Varity_R		0.59
gMVP		0.41
Mutation Taster		=42/58	disease causing

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: rs140308315; hg19: chr5-145979873;