chr6-42984685-A-T

Variant names:

• chr6-42984685-A-T
• NM_006245.4:c.8A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_006245.4(PPP2R5D):​c.8A>T​(p.Tyr3Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000048 in 1,459,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PPP2R5D NM_006245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.66
• Publications: 0 publications found

Genes affected

PPP2R5D (HGNC:9312): (protein phosphatase 2 regulatory subunit B'delta) 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 delta isoform of the regulatory subunit B56 subfamily. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

PPP2R5D Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Hogue-Janssens syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32083628).
• BP6: Variant 6-42984685-A-T is Benign according to our data. Variant chr6-42984685-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1208150.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006245.4. 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
	PPP2R5D	NM_006245.4	MANE Select	c.8A>T	p.Tyr3Phe	missense	Exon 1 of 16	NP_006236.1	Q14738-1
	PPP2R5D	NM_180976.3		c.8A>T	p.Tyr3Phe	missense	Exon 1 of 16	NP_851307.1	Q14738-2
	PPP2R5D	NM_180977.3		c.8A>T	p.Tyr3Phe	missense	Exon 1 of 14	NP_851308.1	Q14738-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R5D	ENST00000485511.6	TSL:1 MANE Select	c.8A>T	p.Tyr3Phe	missense	Exon 1 of 16	ENSP00000417963.1	Q14738-1
	PPP2R5D	ENST00000394110.7	TSL:1	c.8A>T	p.Tyr3Phe	missense	Exon 1 of 16	ENSP00000377669.3	Q14738-2
	PPP2R5D	ENST00000461010.5	TSL:1	c.8A>T	p.Tyr3Phe	missense	Exon 1 of 14	ENSP00000420674.1	Q14738-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459088 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 725742

African (AFR) AF: 0.00 AC: 0 AN: 33322

American (AMR) AF: 0.00 AC: 0 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 85746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110960

Other (OTH) AF: 0.00 AC: 0 AN: 60194

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Benign	0.93
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.019
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.35	N
PhyloP100		4.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.19
Sift	Benign	0.054	T
Sift4G	Uncertain	0.060	T
Polyphen		0.084	B
Vest4		0.57
MutPred		0.14		Loss of phosphorylation at Y3 (P = 0.0161)
MVP		0.52
MPC		1.2
ClinPred		0.52	D
GERP RS		5.2
PromoterAI		-0.040	Neutral
Varity_R		0.17
gMVP		0.18
Mutation Taster		=80/20	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

hg19: chr6-42952423;