NM_002706.6:c.847G>A

Variant names:

• chr2-44209210-G-A
• NM_002706.6:c.847G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002706.6(PPM1B):​c.847G>A​(p.Gly283Arg) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPM1B NM_002706.6 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.92
• Publications: 0 publications found

Genes affected

PPM1B (HGNC:9276): (protein phosphatase, Mg2+/Mn2+ dependent 1B) The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell stress response pathways. This phosphatase has been shown to dephosphorylate cyclin-dependent kinases (CDKs), and thus may be involved in cell cycle control. Overexpression of this phosphatase is reported to cause cell-growth arrest or cell death. Alternative splicing results in multiple transcript variants encoding different isoforms. Additional transcript variants have been described, but currently do not represent full-length sequences. [provided by RefSeq, Jul 2008]

ENSG00000285542 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002706.6. 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
	PPM1B	NM_002706.6	MANE Select	c.847G>A	p.Gly283Arg	missense splice_region	Exon 3 of 6	NP_002697.1	O75688-1
	PPM1B	NM_177968.4		c.847G>A	p.Gly283Arg	missense splice_region	Exon 3 of 6	NP_808907.1	O75688-2
	PPM1B	NM_001033557.3		c.847G>A	p.Gly283Arg	missense splice_region	Exon 3 of 6	NP_001028729.1	O75688-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1B	ENST00000282412.9	TSL:1 MANE Select	c.847G>A	p.Gly283Arg	missense splice_region	Exon 3 of 6	ENSP00000282412.4	O75688-1
	PPM1B	ENST00000378551.6	TSL:1	c.847G>A	p.Gly283Arg	missense splice_region	Exon 3 of 6	ENSP00000367813.2	O75688-2
	PPM1B	ENST00000409432.7	TSL:1	c.847G>A	p.Gly283Arg	missense splice_region	Exon 3 of 6	ENSP00000387287.3	O75688-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.69		Gain of ubiquitination at K282 (P = 0.07)
MVP		0.76
MPC		0.70
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.73
Mutation Taster		=140/160	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.11		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

hg19: chr2-44436349;