1-212348405-G-A

Position:

• chr1-212348405-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006243.4(PPP2R5A):​c.781G>A​(p.Ala261Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPP2R5A NM_006243.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.80

Genes affected

PPP2R5A (HGNC:9309): (protein phosphatase 2 regulatory subunit B'alpha) The product of 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 alpha isoform of the regulatory subunit B56 subfamily. Alternative transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R5A	NM_006243.4	c.781G>A	p.Ala261Thr	missense_variant	7/13	ENST00000261461.7	NP_006234.1
PPP2R5A	NM_001199756.2	c.610G>A	p.Ala204Thr	missense_variant	7/13		NP_001186685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R5A	ENST00000261461.7	c.781G>A	p.Ala261Thr	missense_variant	7/13	1	NM_006243.4	ENSP00000261461	P1
PPP2R5A	ENST00000537030.3	c.610G>A	p.Ala204Thr	missense_variant	7/13	2		ENSP00000442866

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

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

Apr 18, 2024

The c.781G>A (p.A261T) alteration is located in exon 7 (coding exon 7) of the PPP2R5A gene. This alteration results from a G to A substitution at nucleotide position 781, causing the alanine (A) at amino acid position 261 to be replaced by a threonine (T). 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	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.0080	T
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.036	D;D
Polyphen		0.28	B;.
Vest4		0.74
MutPred		0.86		Loss of ubiquitination at K265 (P = 0.0736);.;
MVP		0.50
MPC		1.2
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr1-212521747;