chr11-111737534-C-G

Variant names:

• chr11-111737534-C-G
• rs45568137
• ENST00000311129.9:c.1825G>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_181699.3(PPP2R1B):​c.1825G>C​(p.Val609Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 1,614,216 control chromosomes in the GnomAD database, including 1,326 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.028 (128 hom., cov: 33)
  • Exomes 𝑓: 0.037 (1198 hom.)
• Consequence: PPP2R1B NM_181699.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.09

Genes affected

PPP2R1B (HGNC:9303): (protein phosphatase 2 scaffold subunit Abeta) 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 a beta isoform of the constant regulatory subunit A. Mutations in this gene have been associated with some lung and colon cancers. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020316243).
• BP6: Variant 11-111737534-C-G is Benign according to our data. Variant chr11-111737534-C-G is described in ClinVar as [Benign]. Clinvar id is 3057072.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R1B	NM_181699.3	c.1825G>C	p.Val609Leu	missense_variant	Exon 15 of 16		NP_859050.1
PPP2R1B	NM_181700.2	c.1633G>C	p.Val545Leu	missense_variant	Exon 13 of 14		NP_859051.1
PPP2R1B	XM_047427196.1	c.1825G>C	p.Val609Leu	missense_variant	Exon 15 of 16		XP_047283152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R1B	ENST00000311129.9	c.1825G>C	p.Val609Leu	missense_variant	Exon 15 of 16	1		ENSP00000311344.5
PPP2R1B	ENST00000426998.6	c.1633G>C	p.Val545Leu	missense_variant	Exon 13 of 14	2		ENSP00000410671.2
PPP2R1B	ENST00000526287.1	n.-31G>C		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 4326 AN: 152216 Hom.: 128 Cov.: 33

Gnomad AFR AF: 0.00808

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0806

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0344

Gnomad FIN AF: 0.0246

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0331

Gnomad OTH AF: 0.0205

GnomAD3 exomes AF: 0.0343 AC: 8621 AN: 251466 Hom.: 261 AF XY: 0.0343 AC XY: 4666 AN XY: 135910

Gnomad AFR exome AF: 0.00738

Gnomad AMR exome AF: 0.0809

Gnomad ASJ exome AF: 0.00744

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0394

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.0322

Gnomad OTH exome AF: 0.0367

GnomAD4 exome AF: 0.0365 AC: 53372 AN: 1461882 Hom.: 1198 Cov.: 31 AF XY: 0.0367 AC XY: 26673 AN XY: 727244

Gnomad4 AFR exome AF: 0.00517

Gnomad4 AMR exome AF: 0.0789

Gnomad4 ASJ exome AF: 0.00658

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0427

Gnomad4 FIN exome AF: 0.0214

Gnomad4 NFE exome AF: 0.0383

Gnomad4 OTH exome AF: 0.0313

GnomAD4 genome AF: 0.0284 AC: 4326 AN: 152334 Hom.: 128 Cov.: 33 AF XY: 0.0290 AC XY: 2159 AN XY: 74494

Gnomad4 AFR AF: 0.00806

Gnomad4 AMR AF: 0.0805

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0348

Gnomad4 FIN AF: 0.0246

Gnomad4 NFE AF: 0.0331

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.0304 Hom.: 68

Bravo AF: 0.0300

TwinsUK AF: 0.0429 AC: 159

ALSPAC AF: 0.0439 AC: 169

ESP6500AA AF: 0.0129 AC: 57

ESP6500EA AF: 0.0350 AC: 301

ExAC AF: 0.0314 AC: 3818

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0328

EpiControl AF: 0.0338

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PPP2R1B-related disorder Benign:1

Nov 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.052
Sift	Uncertain	0.017	D;D
Sift4G	Benign	0.091	T;T
Polyphen		0.0	B;.
Vest4		0.064
MutPred		0.23		Loss of methylation at K610 (P = 0.0725);.;
MPC		0.23
ClinPred		0.021	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45568137; hg19: chr11-111608258; COSMIC: COSV99064490; COSMIC: COSV99064490;