2-44202017-A-T

Variant names:

• chr2-44202017-A-T
• rs767149331
• NM_002706.6:c.818A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002706.6(PPM1B):​c.818A>T​(p.Asn273Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,451,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N273S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PPM1B NM_002706.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPM1B	NM_002706.6	c.818A>T	p.Asn273Ile	missense_variant	Exon 2 of 6	ENST00000282412.9	NP_002697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPM1B	ENST00000282412.9	c.818A>T	p.Asn273Ile	missense_variant	Exon 2 of 6	1	NM_002706.6	ENSP00000282412.4
ENSG00000285542	ENST00000649044.1	n.818A>T		non_coding_transcript_exon_variant	Exon 2 of 15			ENSP00000497083.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1451142 Hom.: 0 Cov.: 31 AF XY: 0.00000416 AC XY: 3 AN XY: 720774

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: 0.00000181

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000227 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	.;.;T;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.4	.;M;M;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.4	D;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D
Polyphen		0.98, 0.86	.;.;D;P
Vest4		0.86, 0.85, 0.86
MutPred		0.54		Loss of catalytic residue at N273 (P = 0.184);Loss of catalytic residue at N273 (P = 0.184);Loss of catalytic residue at N273 (P = 0.184);Loss of catalytic residue at N273 (P = 0.184);
MVP		0.75
MPC		0.71
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.95
gMVP		0.56

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

LitVar

Other links and lift over

dbSNP: rs767149331; hg19: chr2-44429156;