17-58756362-C-T

Variant names:

• chr17-58756362-C-T
• rs936724323
• NM_014906.5:c.365C>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.365C>T​(p.Pro122Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000291 in 1,376,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P122Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: PPM1E NM_014906.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.32
• 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]

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=0.23609492).

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.365C>T	p.Pro122Leu	missense	Exon 1 of 7	NP_055721.3
	PPM1E	NR_048561.1		n.494C>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.365C>T	p.Pro122Leu	missense	Exon 1 of 7	ENSP00000312411.2	Q8WY54-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151936 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000349 AC: 1 AN: 28686 AF XY: 0.0000686

Gnomad AFR exome AF: 0.000651

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000245 AC: 3 AN: 1224880 Hom.: 0 Cov.: 33 AF XY: 0.00000335 AC XY: 2 AN XY: 596936

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

African (AFR) AF: 0.0000421 AC: 1 AN: 23780

American (AMR) AF: 0.00 AC: 0 AN: 11818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16814

East Asian (EAS) AF: 0.00 AC: 0 AN: 27636

South Asian (SAS) AF: 0.0000204 AC: 1 AN: 48940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3380

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 999844

Other (OTH) AF: 0.00 AC: 0 AN: 49772

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0556734), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151936 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74204

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.0000656 AC: 1 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67942

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0041	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.082
Sift	Benign	0.48	T
Sift4G	Benign	0.20	T
Vest4		0.42
MutPred		0.22		Loss of glycosylation at P122 (P = 0.004)
MVP		0.21
MPC		1.1
ClinPred		0.15	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.078
gMVP		0.18
Mutation Taster		=90/10	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: rs936724323; hg19: chr17-56833723;