rs786201011

chr12-12718210-ACT-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_004064.5(CDKN1B):c.374_375del(p.Ser125Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N124N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN1B NM_004064.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.33

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 12-12718210-ACT-A is Pathogenic according to our data. Variant chr12-12718210-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 183395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1B	NM_004064.5	c.374_375del	p.Ser125Ter	frameshift_variant	1/3	ENST00000228872.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1B	ENST00000228872.9	c.374_375del	p.Ser125Ter	frameshift_variant	1/3	1	NM_004064.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 4 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 21, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 183395). This premature translational stop signal has been observed in individual(s) with clinical features of multiple endocrine neoplasia 4 (PMID: 24819502). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser125*) in the CDKN1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKN1B are known to be pathogenic (PMID: 17030811, 24819502). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2023

The c.374_375delCT pathogenic mutation, located in coding exon 1 of the CDKN1B gene, results from a deletion of two nucleotides at nucleotide positions 374 to 375, causing a translational frameshift with a predicted alternate stop codon (p.S125*). This alteration was observed in multiple individuals with a personal history that is consistent with multiple endocrine neoplasia type 4 (MEN4) (Tonelli F et al. Eur J Endocrinol, 2014 Aug;171:K7-K17; Pardi E et al. Endocr Connect, 2015 Mar;4:1-8; Seabrook A et al. J Clin Endocrinol Metab, 2022 Jul;107:2339-2349). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

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: rs786201011; hg19: chr12-12871144;