22-50443885-C-A

Variant names:

• chr22-50443885-C-A
• rs200415574
• NM_001242898.2:c.2599C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001242898.2(PPP6R2):​c.2599C>A​(p.Arg867Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,431,440 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: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PPP6R2 NM_001242898.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.222
• 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP7: Synonymous conserved (PhyloP=0.222 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242898.2. 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.2599C>A	p.Arg867Arg	synonymous	Exon 23 of 24	NP_001229827.1	O75170-5
	PPP6R2	NM_001365836.1		c.2620C>A	p.Arg874Arg	synonymous	Exon 25 of 26	NP_001352765.1	O75170-1
	PPP6R2	NM_001351641.2		c.2602C>A	p.Arg868Arg	synonymous	Exon 23 of 24	NP_001338570.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP6R2	ENST00000612753.5	TSL:2 MANE Select	c.2599C>A	p.Arg867Arg	synonymous	Exon 23 of 24	ENSP00000478417.1	O75170-5
	PPP6R2	ENST00000216061.9	TSL:1	c.2620C>A	p.Arg874Arg	synonymous	Exon 24 of 25	ENSP00000216061.5	O75170-1
	PPP6R2	ENST00000395741.7	TSL:1	c.2521C>A	p.Arg841Arg	synonymous	Exon 22 of 23	ENSP00000379090.3	O75170-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1431440 Hom.: 0 Cov.: 30 AF XY: 0.00000282 AC XY: 2 AN XY: 709624

African (AFR) AF: 0.00 AC: 0 AN: 32638

American (AMR) AF: 0.00 AC: 0 AN: 41386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25612

East Asian (EAS) AF: 0.00 AC: 0 AN: 37854

South Asian (SAS) AF: 0.00 AC: 0 AN: 82922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5070

European-Non Finnish (NFE) AF: 0.00000365 AC: 4 AN: 1096842

Other (OTH) AF: 0.00 AC: 0 AN: 59012

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.63
DANN	Benign	0.59
PhyloP100		0.22
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200415574; hg19: chr22-50882314;