rs1060500186

Positions:

• chr12-12717886-TGGAC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004064.5(CDKN1B):​c.49_52del​(p.Asp17ProfsTer24) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDKN1B NM_004064.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.80

Genes affected

CDKN1B (HGNC:1785): (cyclin dependent kinase inhibitor 1B) This gene encodes a cyclin-dependent kinase inhibitor, which shares a limited similarity with CDK inhibitor CDKN1A/p21. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. The degradation of this protein, which is triggered by its CDK dependent phosphorylation and subsequent ubiquitination by SCF complexes, is required for the cellular transition from quiescence to the proliferative state. Mutations in this gene are associated with multiple endocrine neoplasia type IV (MEN4). [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 46 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-12717886-TGGAC-T is Pathogenic according to our data. Variant chr12-12717886-TGGAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 404266.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1B	NM_004064.5	c.49_52del	p.Asp17ProfsTer24	frameshift_variant	1/3	ENST00000228872.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1B	ENST00000228872.9	c.49_52del	p.Asp17ProfsTer24	frameshift_variant	1/3	1	NM_004064.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple endocrine neoplasia type 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 21, 2016

This sequence change deletes 4 nucleotides from exon 1 of the CDKN1B mRNA (c.49_52delGACG), causing a frameshift at codon 17. This creates a premature translational stop signal (p.Asp17Profs*24) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in CDKN1B are known to be pathogenic (PMID: 17030811, 24819502). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs1060500186; hg19: chr12-12870820;