chr14-101882239-CCAA-C

Variant names:

• chr14-101882239-CCAA-C
• rs869320755
• NM_001352913.2:c.540_542delAAC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_001352913.2(PPP2R5C):​c.540_542delAAC​(p.Thr181del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPP2R5C NM_001352913.2 disruptive_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32
• Publications: 2 publications found

Genes affected

PPP2R5C (HGNC:9311): (protein phosphatase 2 regulatory subunit B'gamma) The product of this gene belongs to the phosphatase 2A regulatory subunit B family. Protein phosphatase 2A is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. The B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a gamma isoform of the regulatory subunit B56 subfamily. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

PPP2R5C Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001352913.2
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001352913.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 14-101882239-CCAA-C is Pathogenic according to our data. Variant chr14-101882239-CCAA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 217454.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352913.2. 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
	PPP2R5C	NM_001352913.2	MANE Select	c.540_542delAAC	p.Thr181del	disruptive_inframe_deletion	Exon 5 of 16	NP_001339842.1	A0A8Q3WKR3
	PPP2R5C	NM_001161725.2		c.468_470delAAC	p.Thr157del	disruptive_inframe_deletion	Exon 5 of 16	NP_001155197.1	Q13362-5
	PPP2R5C	NM_001352914.2		c.555_557delAAC	p.Thr186del	disruptive_inframe_deletion	Exon 5 of 15	NP_001339843.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R5C	ENST00000694906.1	MANE Select	c.540_542delAAC	p.Thr181del	disruptive_inframe_deletion	Exon 5 of 16	ENSP00000511581.1	A0A8Q3WKR3
	PPP2R5C	ENST00000334743.9	TSL:1	c.375_377delAAC	p.Thr126del	disruptive_inframe_deletion	Exon 3 of 14	ENSP00000333905.4	Q13362-1
	PPP2R5C	ENST00000350249.7	TSL:1	c.375_377delAAC	p.Thr126del	disruptive_inframe_deletion	Exon 3 of 13	ENSP00000262239.5	Q13362-3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=30/70	disease causing

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: rs869320755; hg19: chr14-102348576;