rs774454456

chr12-12717807-CGAGA-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_004064.5(CDKN1B):c.-29_-26del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,609,190 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (1 hom.)
• Consequence: CDKN1B NM_004064.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3 B:5
• Conservation: PhyloP100: 1.65

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 12-12717807-CGAGA-C is Benign according to our data. Variant chr12-12717807-CGAGA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217126.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3, Pathogenic=1}.
• BS2: High AC in GnomAd at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1B	NM_004064.5	c.-29_-26del		5_prime_UTR_variant	1/3	ENST00000228872.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1B	ENST00000228872.9	c.-29_-26del		5_prime_UTR_variant	1/3	1	NM_004064.5	P1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152108 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000376 AC: 92 AN: 244842 Hom.: 0 AF XY: 0.000463 AC XY: 62 AN XY: 133778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000643

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000581 AC: 846 AN: 1456964 Hom.: 1 AF XY: 0.000584 AC XY: 423 AN XY: 724762

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000177

Gnomad4 NFE exome AF: 0.000699

Gnomad4 OTH exome AF: 0.000399

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.000390 AC XY: 29 AN XY: 74424

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000564 Hom.: 0

Bravo AF: 0.000548

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple endocrine neoplasia type 4 Pathogenic:1 Benign:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	CDKN1B: PS3:Moderate, BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2023	Published functional studies demonstrate a damaging effect: decreased transcriptional activity, reduced p27 mRNA, and increased cytoplasmic localization (PMID: 22129891, 25645465, 27038812); Deleted nucleotides are not conserved across species; Also known as c.-32_-29del; This variant is associated with the following publications: (PMID: 27038812, 28824003, 25645465, 26054904, 27657986, 24819502, 30555957, 32232325, 34426522, 30065701, 22129891, 35355569, 30990521, 36520683) -

Primary hyperparathyroidism Pathogenic:1

Pathogenic, flagged submission

in vitro;research

Endocrine Unit 2, University Hospital of Pisa

Jan 01, 2015

- -

CDKN1B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Multiple endocrine neoplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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: rs774454456; hg19: chr12-12870741;