2-44201677-G-A

Variant summary

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

The NM_002706.6(PPM1B):c.478G>A(p.Gly160Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PPM1B NM_002706.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38

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]

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, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPM1B	NM_002706.6	c.478G>A	p.Gly160Arg	missense_variant	2/6	ENST00000282412.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPM1B	ENST00000282412.9	c.478G>A	p.Gly160Arg	missense_variant	2/6	1	NM_002706.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jul 12, 2022

The c.478G>A (p.G160R) alteration is located in exon 2 (coding exon 1) of the PPM1B gene. This alteration results from a G to A substitution at nucleotide position 478, causing the glycine (G) at amino acid position 160 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	Benign	0.20
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.6	D;D;D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.17	T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		0.31, 0.79	.;.;B;P;.
Vest4		0.45, 0.53
MutPred		0.79		Gain of solvent accessibility (P = 0.0263);Gain of solvent accessibility (P = 0.0263);Gain of solvent accessibility (P = 0.0263);Gain of solvent accessibility (P = 0.0263);Gain of solvent accessibility (P = 0.0263);
MVP		0.66
MPC		0.28
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.64
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs1187789520; hg19: chr2-44428816;