22-50444214-G-T

Variant names:

• chr22-50444214-G-T
• NM_001242898.2:c.2847G>T
• PPP6R2 p.Pro949Pro

Variant summary

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

The NM_001242900.2(PPP6R2):​c.2765G>T​(p.Arg922Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict 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. R922H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PPP6R2 NM_001242900.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.919
• Publications: 0 publications found

Genes affected

PPP6R2 (HGNC:19253): (protein phosphatase 6 regulatory subunit 2) The protein encoded by this gene is a regulatory protein for the protein phosphatase-6 catalytic subunit. Together, these proteins act as a significant T-loop phosphatase for Aurora A, an essential mitotic kinase. Loss of function of either the regulatory or catalytic subunit of protein phosphatase-6 interferes with spindle formation and chromosome alignment. [provided by RefSeq, May 2017]

SBF1 (HGNC:10542): (SET binding factor 1) This gene encodes a member of the protein-tyrosine phosphatase family. However, the encoded protein does not appear to be a catalytically active phosphatase because it lacks several amino acids in the catalytic pocket. This protein contains a Guanine nucleotide exchange factor (GEF) domain which is necessary for its role in growth and differentiation. Mutations in this gene have been associated with Charcot-Marie-Tooth disease 4B3. Pseudogenes of this gene have been defined on chromosomes 1 and 8. [provided by RefSeq, Dec 2014]

SBF1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 4B3

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen

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 (MetaRNN=0.058886617).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242900.2. 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
	PPP6R2	NM_001242898.2	MANE Select	c.2847G>T	p.Pro949Pro	synonymous	Exon 24 of 24	NP_001229827.1	O75170-5
	PPP6R2	NM_001242900.2		c.2765G>T	p.Arg922Leu	missense	Exon 23 of 23	NP_001229829.1	O75170-2
	PPP6R2	NM_001365836.1		c.2868G>T	p.Pro956Pro	synonymous	Exon 26 of 26	NP_001352765.1	O75170-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP6R2	ENST00000612753.5	TSL:2 MANE Select	c.2847G>T	p.Pro949Pro	synonymous	Exon 24 of 24	ENSP00000478417.1	O75170-5
	PPP6R2	ENST00000216061.9	TSL:1	c.2868G>T	p.Pro956Pro	synonymous	Exon 25 of 25	ENSP00000216061.5	O75170-1
	PPP6R2	ENST00000395741.7	TSL:1	c.2769G>T	p.Pro923Pro	synonymous	Exon 23 of 23	ENSP00000379090.3	O75170-3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.16
DANN	Benign	0.79
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.92
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.018
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr22-50882643;