NM_002706.6:c.831C>A

Variant names:

• chr2-44202030-C-A
• rs201318610
• NM_002706.6:c.831C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002706.6(PPM1B):​c.831C>A​(p.Asp277Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,415,222 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PPM1B NM_002706.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.60
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.831C>A	p.Asp277Glu	missense	Exon 2 of 6	NP_002697.1	O75688-1
	PPM1B	NM_177968.4		c.831C>A	p.Asp277Glu	missense	Exon 2 of 6	NP_808907.1	O75688-2
	PPM1B	NM_001033557.3		c.831C>A	p.Asp277Glu	missense	Exon 2 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.831C>A	p.Asp277Glu	missense	Exon 2 of 6	ENSP00000282412.4	O75688-1
	PPM1B	ENST00000378551.6	TSL:1	c.831C>A	p.Asp277Glu	missense	Exon 2 of 6	ENSP00000367813.2	O75688-2
	PPM1B	ENST00000409432.7	TSL:1	c.831C>A	p.Asp277Glu	missense	Exon 2 of 6	ENSP00000387287.3	O75688-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1415222 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 699390

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31586

American (AMR) AF: 0.00 AC: 0 AN: 36142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23774

East Asian (EAS) AF: 0.00 AC: 0 AN: 39146

South Asian (SAS) AF: 0.00 AC: 0 AN: 78370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5538

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090292

Other (OTH) AF: 0.00 AC: 0 AN: 58280

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.24
Sift	Benign	0.041	D
Sift4G	Benign	0.088	T
Polyphen		0.81	P
Vest4		0.75
MutPred		0.56		Gain of ubiquitination at K282 (P = 0.1446)
MVP		0.67
MPC		0.54
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.84
gMVP		0.38
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs201318610; hg19: chr2-44429169;