2-28752031-C-T

Variant names:

• chr2-28752031-C-T
• rs530957503
• NM_002709.3:c.-94C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_002709.3(PPP1CB):​c.-94C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,230,904 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: PPP1CB NM_002709.3 5_prime_UTR
• Scores: Splicing: ADA: 0.004835
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.35
• Publications: 0 publications found

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]

PPP1CB Gene-Disease associations (from GenCC):

• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome-like disorder with loose anagen hair 2

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 2-28752031-C-T is Benign according to our data. Variant chr2-28752031-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1203931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 196 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1CB	NM_002709.3	c.-94C>T		5_prime_UTR_variant	Exon 1 of 8	ENST00000395366.3	NP_002700.1
PPP1CB	NM_206876.2	c.-87-7C>T		splice_region_variant, intron_variant	Intron 1 of 8		NP_996759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1CB	ENST00000395366.3	c.-94C>T		5_prime_UTR_variant	Exon 1 of 8	1	NM_002709.3	ENSP00000378769.2

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152034 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00187 AC: 2016 AN: 1078754 Hom.: 2 Cov.: 14 AF XY: 0.00181 AC XY: 990 AN XY: 545602

African (AFR) AF: 0.000283 AC: 7 AN: 24710

American (AMR) AF: 0.000767 AC: 27 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.000604 AC: 14 AN: 23182

East Asian (EAS) AF: 0.0000891 AC: 3 AN: 33676

South Asian (SAS) AF: 0.00 AC: 0 AN: 72712

European-Finnish (FIN) AF: 0.000435 AC: 21 AN: 48242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5030

European-Non Finnish (NFE) AF: 0.00240 AC: 1893 AN: 788792

Other (OTH) AF: 0.00108 AC: 51 AN: 47226

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152150 Hom.: 0 Cov.: 30 AF XY: 0.00106 AC XY: 79 AN XY: 74390

African (AFR) AF: 0.000458 AC: 19 AN: 41510

American (AMR) AF: 0.000719 AC: 11 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00221 AC: 150 AN: 67992

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000583 Hom.: 0

Bravo AF: 0.00135

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 24, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.96
PhyloP100		1.4
PromoterAI		-0.17	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0048
dbscSNV1_RF	Benign	0.058
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: rs530957503; hg19: chr2-28974897; COSMIC: COSV56090066;