2-28752031-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002709.3(PPP1CB):​c.-94C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000927 in 1,078,768 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 30)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: PPP1CB NM_002709.3 5_prime_UTR
• Scores: Splicing: ADA: 0.002874
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1CB	NM_002709.3	c.-94C>A		5_prime_UTR_variant	Exon 1 of 8	ENST00000395366.3	NP_002700.1
PPP1CB	NM_206876.2	c.-87-7C>A		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>A		5_prime_UTR_variant	Exon 1 of 8	1	NM_002709.3	ENSP00000378769.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 9.27e-7 AC: 1 AN: 1078768 Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0 AN XY: 545614

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24710

American (AMR) AF: 0.00 AC: 0 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23182

East Asian (EAS) AF: 0.00 AC: 0 AN: 33676

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48242

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

European-Non Finnish (NFE) AF: 0.00000127 AC: 1 AN: 788806

Other (OTH) AF: 0.00 AC: 0 AN: 47226

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Benign	0.94
PhyloP100		1.4
PromoterAI		-0.35	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0029
dbscSNV1_RF	Benign	0.10
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;