14-63539640-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_006246.5(PPP2R5E):c.46G>A(p.Gly16Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PPP2R5E NM_006246.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.42

Genes affected

PPP2R5E (HGNC:9313): (protein phosphatase 2 regulatory subunit B'epsilon) The protein encoded by this gene belongs to the phosphatase 2A regulatory subunit B family. Protein phosphatase 2A 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 an epsilon isoform of the regulatory subunit B56 subfamily. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PPP2R5E

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP2R5E	NM_006246.5	c.46G>A	p.Gly16Arg	missense_variant	2/14	ENST00000337537.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP2R5E	ENST00000337537.8	c.46G>A	p.Gly16Arg	missense_variant	2/14	1	NM_006246.5	P1
PPP2R5E	ENST00000555899.1	c.46G>A	p.Gly16Arg	missense_variant	2/14	1
PPP2R5E	ENST00000553266.5	n.629G>A		non_coding_transcript_exon_variant	2/12	1
PPP2R5E	ENST00000556878.1	n.648G>A		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461724 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2022

The c.46G>A (p.G16R) alteration is located in exon 2 (coding exon 1) of the PPP2R5E gene. This alteration results from a G to A substitution at nucleotide position 46, causing the glycine (G) at amino acid position 16 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.0070	T
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.22
Sift	Benign	0.15	T;T
Sift4G	Benign	0.53	T;T
Polyphen		1.0	D;.
Vest4		0.68
MutPred		0.26		Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);
MVP		0.40
MPC		2.2
ClinPred		0.91	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.23
gMVP		0.68

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-64006358; COSMIC: COSV61741602; COSMIC: COSV61741602;