chr12-12717383-CCCTT-C

Variant names:

• chr12-12717383-CCCTT-C
• rs786201010
• NM_004064.5:c.-454_-451delTTCC

Variant summary

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

The NM_004064.5(CDKN1B):​c.-454_-451delTTCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000196 in 1,019,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: CDKN1B NM_004064.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.55
• Publications: 6 publications found

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]

GPR19 (HGNC:4473): (G protein-coupled receptor 19) Predicted to enable G protein-coupled receptor activity. Predicted to be involved in G protein-coupled receptor signaling pathway. Located in cilium. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1B	NM_004064.5	c.-454_-451delTTCC		5_prime_UTR_variant	Exon 1 of 3	ENST00000228872.9	NP_004055.1
GPR19	XM_011520623.4	c.-1881_-1878delAAGG		upstream_gene_variant			XP_011518925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1B	ENST00000228872.9	c.-454_-451delTTCC		5_prime_UTR_variant	Exon 1 of 3	1	NM_004064.5	ENSP00000228872.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000196 AC: 2 AN: 1019002 Hom.: 0 AF XY: 0.00000209 AC XY: 1 AN XY: 478606

African (AFR) AF: 0.00 AC: 0 AN: 21748

American (AMR) AF: 0.00 AC: 0 AN: 7696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12222

East Asian (EAS) AF: 0.00 AC: 0 AN: 19090

South Asian (SAS) AF: 0.00 AC: 0 AN: 36564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2468

European-Non Finnish (NFE) AF: 0.00000229 AC: 2 AN: 874022

Other (OTH) AF: 0.00 AC: 0 AN: 39086

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple endocrine neoplasia type 4 Pathogenic:1

Mar 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome Uncertain:1

May 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-454_-451delTTCC variant is located in the 5' untranslated region (5'UTR) of the CDKN1B gene. This variant results from a deletion of four nucleotides 451 nucleotides upstream from the first translated codon. This variant has been observed in at least one individual with a personal and/or family history that is consistent with CDKN1B-related multiple endocrine neoplasia (Occhi G et al. PLoS Genet, 2013 Mar;9:e1003350). Functional studies have demonstrated an inhibitory effect of this variant on CDKN1B expression (Occhi G et al. PLoS Genet, 2013 Mar;9:e1003350).. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5
Mutation Taster		=72/228	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786201010; hg19: chr12-12870317;