NM_014225.6:c.656C>T

Variant names:

• chr19-52212959-C-T
• rs1555791268
• NM_014225.6:c.656C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_014225.6(PPP2R1A):​c.656C>T​(p.Ser219Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S219P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP2R1A NM_014225.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 4.11
• Publications: 1 publications found

Genes affected

PPP2R1A (HGNC:9302): (protein phosphatase 2 scaffold subunit Aalpha) This gene encodes a constant regulatory subunit of protein phosphatase 2. Protein phosphatase 2 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 constant regulatory subunit A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. This gene encodes an alpha isoform of the constant regulatory subunit A. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2010]

PPP2R1A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Houge-Janssens syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-52212958-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 916077.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• PP5: Variant 19-52212959-C-T is Pathogenic according to our data. Variant chr19-52212959-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 521503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014225.6. 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
	PPP2R1A	NM_014225.6	MANE Select	c.656C>T	p.Ser219Leu	missense	Exon 6 of 15	NP_055040.2
	PPP2R1A	NM_001363656.2		c.119C>T	p.Ser40Leu	missense	Exon 6 of 15	NP_001350585.1	B3KQV6
	PPP2R1A	NR_033500.2		n.600C>T		non_coding_transcript_exon	Exon 5 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1A	ENST00000322088.11	TSL:1 MANE Select	c.656C>T	p.Ser219Leu	missense	Exon 6 of 15	ENSP00000324804.6	P30153
	PPP2R1A	ENST00000454220.7	TSL:1	c.776C>T	p.Ser259Leu	missense	Exon 6 of 15	ENSP00000391905.3	C9J9C1
	PPP2R1A	ENST00000703398.1		c.698C>T	p.Ser233Leu	missense	Exon 6 of 15	ENSP00000515288.1	A0A994J3H1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1442742 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716340

African (AFR) AF: 0.00 AC: 0 AN: 33116

American (AMR) AF: 0.00 AC: 0 AN: 42726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24402

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 82596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102986

Other (OTH) AF: 0.00 AC: 0 AN: 59608

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Houge-Janssens syndrome 2 (8)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	PPP2R1A-related disorder (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.77		Loss of disorder (P = 0.0233)
MVP		0.77
MPC		2.4
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.88
Mutation Taster		=10/90	disease causing (ClinVar)

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: rs1555791268; hg19: chr19-52716212; COSMIC: COSV59042650; COSMIC: COSV59042650;