chr17-58756341-C-T

Variant names:

• chr17-58756341-C-T
• rs2049763764
• NM_014906.5:c.344C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014906.5(PPM1E):​c.344C>T​(p.Pro115Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000082 in 1,220,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P115S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: PPM1E NM_014906.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.717
• Publications: 0 publications found

Genes affected

PPM1E (HGNC:19322): (protein phosphatase, Mg2+/Mn2+ dependent 1E) This gene encodes a member of the PPM family of serine/threonine-protein phosphatases. The encoded protein is localized to the nucleus and dephosphorylates and inactivates multiple substrates including serine/threonine-protein kinase PAK 1, 5'-AMP-activated protein kinase (AMPK) and the multifunctional calcium/calmodulin-dependent protein kinases. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2012]

LOC105371843 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22845083).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014906.5. 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
	PPM1E	NM_014906.5	MANE Select	c.344C>T	p.Pro115Leu	missense	Exon 1 of 7	NP_055721.3
	PPM1E	NR_048561.1		n.473C>T		non_coding_transcript_exon	Exon 1 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1E	ENST00000308249.4	TSL:1 MANE Select	c.344C>T	p.Pro115Leu	missense	Exon 1 of 7	ENSP00000312411.2	Q8WY54-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.20e-7 AC: 1 AN: 1220244 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 594126

African (AFR) AF: 0.00 AC: 0 AN: 23692

American (AMR) AF: 0.00 AC: 0 AN: 11442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16636

East Asian (EAS) AF: 0.00 AC: 0 AN: 27648

South Asian (SAS) AF: 0.00 AC: 0 AN: 48250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3338

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 997940

Other (OTH) AF: 0.00 AC: 0 AN: 49560

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0057	T
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.046
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.72
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.027
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.019	D
Vest4		0.31
MutPred		0.25		Loss of glycosylation at P115 (P = 0.0071)
MVP		0.043
MPC		1.1
ClinPred		0.74	D
GERP RS		3.4
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.099
gMVP		0.30
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs2049763764; hg19: chr17-56833702;