22-21923481-C-G

Variant names:

• chr22-21923481-C-G
• rs371072792
• NM_014634.4:c.986-10G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014634.4(PPM1F):​c.986-10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,384 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PPM1F NM_014634.4 intron
• Scores: Splicing: ADA: 0.00001511
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.417
• Publications: 0 publications found

Genes affected

PPM1F (HGNC:19388): (protein phosphatase, Mg2+/Mn2+ dependent 1F) 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 can interact with Rho guanine nucleotide exchange factors (PIX), and thus block the effects of p21-activated kinase 1 (PAK), a protein kinase mediating biological effects downstream of Rho GTPases. Calcium/calmodulin-dependent protein kinase II gamma (CAMK2G/CAMK-II) is found to be one of the substrates of this phosphatase. The overexpression of this phosphatase or CAMK2G has been shown to mediate caspase-dependent apoptosis. An alternatively spliced transcript variant has been identified, but its full-length nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014634.4. 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
	PPM1F	NM_014634.4	MANE Select	c.986-10G>C		intron	N/A	NP_055449.1	P49593-1
	PPM1F	NM_001410836.1		c.482-10G>C		intron	N/A	NP_001397765.1	B5MCT7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1F	ENST00000263212.10	TSL:1 MANE Select	c.986-10G>C		intron	N/A	ENSP00000263212.5	P49593-1
	PPM1F	ENST00000407142.5	TSL:5	c.482-10G>C		intron	N/A	ENSP00000384930.1	B5MCT7
	PPM1F	ENST00000496143.5	TSL:4	n.198-10G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437384 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 711154

⚠️ 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: 33016

American (AMR) AF: 0.00 AC: 0 AN: 43470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39278

South Asian (SAS) AF: 0.00 AC: 0 AN: 84324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5498

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095682

Other (OTH) AF: 0.00 AC: 0 AN: 59156

⚠️ 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
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.7
DANN	Benign	0.53
PhyloP100		-0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0080
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: rs371072792; hg19: chr22-22277854;