2-28752162-C-T

Position:

• chr2-28752162-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_002709.3(PPP1CB):​c.38C>T​(p.Thr13Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,395,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PPP1CB NM_002709.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18

Genes affected

PPP1CB (HGNC:9282): (protein phosphatase 1 catalytic subunit beta) The protein encoded by this gene is one of the three catalytic subunits of protein phosphatase 1 (PP1). PP1 is a serine/threonine specific protein phosphatase known to be involved in the regulation of a variety of cellular processes, such as cell division, glycogen metabolism, muscle contractility, protein synthesis, and HIV-1 viral transcription. Mouse studies suggest that PP1 functions as a suppressor of learning and memory. Two alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PPP1CB. . Gene score misZ 4.3319 (greater than the threshold 3.09). Trascript score misZ 4.7349 (greater than threshold 3.09). GenCC has associacion of gene with Noonan syndrome-like disorder with loose anagen hair 2, Noonan syndrome-like disorder with loose anagen hair.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22953871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP1CB	NM_002709.3	c.38C>T	p.Thr13Ile	missense_variant	1/8	ENST00000395366.3	NP_002700.1
PPP1CB	NM_206876.2	c.38C>T	p.Thr13Ile	missense_variant	2/9		NP_996759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP1CB	ENST00000395366.3	c.38C>T	p.Thr13Ile	missense_variant	1/8	1	NM_002709.3	ENSP00000378769	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1395718 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 688444

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.28e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 12, 2022

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 13 of the PPP1CB protein (p.Thr13Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PPP1CB-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	.;T;T;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.022
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.93	D;D;D;.;.
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	.;.;M;M;M
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Benign	0.085
Sift	Benign	0.067	T;T;D;D;D
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		0.0010	.;.;B;B;B
Vest4		0.30, 0.30, 0.30
MutPred		0.39		Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);
MVP		0.51
MPC		1.8
ClinPred		0.76	D
GERP RS		3.8
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.3
Varity_R		0.16
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs1666312111; hg19: chr2-28975028;