19-52201708-T-C

Variant names:

• chr19-52201708-T-C
• rs10420138
• NM_014225.6:c.79-236T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014225.6(PPP2R1A):​c.79-236T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 517,322 control chromosomes in the GnomAD database, including 51,436 homozygotes. 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: 𝑓 0.47 (17239 hom., cov: 31)
  • Exomes 𝑓: 0.43 (34197 hom.)
• Consequence: PPP2R1A NM_014225.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00300
• Publications: 10 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: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R1A	NM_014225.6	c.79-236T>C		intron_variant	Intron 1 of 14	ENST00000322088.11	NP_055040.2
PPP2R1A	NM_001363656.2	c.-460+14T>C		intron_variant	Intron 1 of 14		NP_001350585.1
PPP2R1A	NR_033500.2	n.124-236T>C		intron_variant	Intron 1 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R1A	ENST00000322088.11	c.79-236T>C		intron_variant	Intron 1 of 14	1	NM_014225.6	ENSP00000324804.6

Frequencies

GnomAD3 genomes AF: 0.468 AC: 70964 AN: 151778 Hom.: 17206 Cov.: 31

Gnomad AFR AF: 0.594

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.445

GnomAD4 exome AF: 0.426 AC: 155617 AN: 365424 Hom.: 34197 Cov.: 2 AF XY: 0.423 AC XY: 81463 AN XY: 192490

African (AFR) AF: 0.595 AC: 6412 AN: 10772

American (AMR) AF: 0.302 AC: 4937 AN: 16344

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 5109 AN: 11214

East Asian (EAS) AF: 0.302 AC: 7518 AN: 24886

South Asian (SAS) AF: 0.380 AC: 16141 AN: 42424

European-Finnish (FIN) AF: 0.438 AC: 9049 AN: 20678

Middle Eastern (MID) AF: 0.457 AC: 1462 AN: 3196

European-Non Finnish (NFE) AF: 0.446 AC: 95913 AN: 214818

Other (OTH) AF: 0.430 AC: 9076 AN: 21092

GnomAD4 genome AF: 0.468 AC: 71052 AN: 151898 Hom.: 17239 Cov.: 31 AF XY: 0.464 AC XY: 34427 AN XY: 74222

African (AFR) AF: 0.594 AC: 24580 AN: 41392

American (AMR) AF: 0.341 AC: 5208 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1567 AN: 3472

East Asian (EAS) AF: 0.321 AC: 1658 AN: 5160

South Asian (SAS) AF: 0.368 AC: 1772 AN: 4812

European-Finnish (FIN) AF: 0.435 AC: 4585 AN: 10542

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30274 AN: 67942

Other (OTH) AF: 0.449 AC: 943 AN: 2102

Alfa AF: 0.450 Hom.: 69817

Bravo AF: 0.466

Asia WGS AF: 0.365 AC: 1270 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.2
DANN	Benign	0.54
PhyloP100		-0.0030
Mutation Taster		=100/0	polymorphism (auto)

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: rs10420138; hg19: chr19-52704961; COSMIC: COSV59044780; COSMIC: COSV59044780;