2-28751725-C-G

Variant names:

• chr2-28751725-C-G
• rs115360250
• ENST00000757369.1:n.52G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000757369.1(PPP1CB-DT):​n.52G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 244,620 control chromosomes in the GnomAD database, including 184 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (179 hom., cov: 31)
  • Exomes 𝑓: 0.0031 (5 hom.)
• Consequence: PPP1CB-DT ENST00000757369.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.07
• Publications: 0 publications found

Genes affected

PPP1CB-DT (HGNC:55829): (PPP1CB divergent transcript)

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-28751725-C-G is Benign according to our data. Variant chr2-28751725-C-G is described in ClinVar as [Benign]. Clinvar id is 1222948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.086 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1CB	NM_002709.3	c.-400C>G		upstream_gene_variant		ENST00000395366.3	NP_002700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1CB	ENST00000395366.3	c.-400C>G		upstream_gene_variant		1	NM_002709.3	ENSP00000378769.2

Frequencies

GnomAD3 genomes AF: 0.0289 AC: 4387 AN: 151984 Hom.: 177 Cov.: 31

Gnomad AFR AF: 0.0881

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.00271

Gnomad OTH AF: 0.0325

GnomAD4 exome AF: 0.00307 AC: 284 AN: 92528 Hom.: 5 Cov.: 0 AF XY: 0.00264 AC XY: 142 AN XY: 53756

African (AFR) AF: 0.0659 AC: 58 AN: 880

American (AMR) AF: 0.0109 AC: 8 AN: 732

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 41 AN: 1942

East Asian (EAS) AF: 0.00 AC: 0 AN: 1442

South Asian (SAS) AF: 0.000243 AC: 5 AN: 20542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5408

Middle Eastern (MID) AF: 0.0274 AC: 9 AN: 328

European-Non Finnish (NFE) AF: 0.00214 AC: 121 AN: 56672

Other (OTH) AF: 0.00917 AC: 42 AN: 4582

GnomAD4 genome AF: 0.0290 AC: 4406 AN: 152092 Hom.: 179 Cov.: 31 AF XY: 0.0288 AC XY: 2145 AN XY: 74358

African (AFR) AF: 0.0884 AC: 3669 AN: 41496

American (AMR) AF: 0.0260 AC: 398 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 71 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10578

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.00268 AC: 182 AN: 67968

Other (OTH) AF: 0.0322 AC: 68 AN: 2114

Alfa AF: 0.0223 Hom.: 15

Bravo AF: 0.0334

Asia WGS AF: 0.00493 AC: 17 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.3
DANN	Benign	0.85
PhyloP100		-1.1
PromoterAI		0.076	Neutral

Splicing

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

Other links and lift over

dbSNP: rs115360250; hg19: chr2-28974591;