12-12717761-T-C

Position:

• chr12-12717761-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004064.5(CDKN1B):​c.-79T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 1,599,978 control chromosomes in the GnomAD database, including 445,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38094 hom., cov: 34)
  • Exomes 𝑓: 0.75 (407359 hom.)
• Consequence: CDKN1B NM_004064.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.109

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-12717761-T-C is Benign according to our data. Variant chr12-12717761-T-C is described in ClinVar as [Benign]. Clinvar id is 307658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN1B	NM_004064.5	c.-79T>C		5_prime_UTR_variant	1/3	ENST00000228872.9	NP_004055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN1B	ENST00000228872.9	c.-79T>C		5_prime_UTR_variant	1/3	1	NM_004064.5	ENSP00000228872	P1

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106549 AN: 152040 Hom.: 38072 Cov.: 34

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.687

Gnomad AMR AF: 0.763

Gnomad ASJ AF: 0.854

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.782

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.757

Gnomad OTH AF: 0.709

GnomAD4 exome AF: 0.748 AC: 1083132 AN: 1447820 Hom.: 407359 Cov.: 73 AF XY: 0.750 AC XY: 539979 AN XY: 720408

Gnomad4 AFR exome AF: 0.568

Gnomad4 AMR exome AF: 0.804

Gnomad4 ASJ exome AF: 0.849

Gnomad4 EAS exome AF: 0.533

Gnomad4 SAS exome AF: 0.786

Gnomad4 FIN exome AF: 0.773

Gnomad4 NFE exome AF: 0.753

Gnomad4 OTH exome AF: 0.740

GnomAD4 genome AF: 0.701 AC: 106625 AN: 152158 Hom.: 38094 Cov.: 34 AF XY: 0.705 AC XY: 52458 AN XY: 74380

Gnomad4 AFR AF: 0.567

Gnomad4 AMR AF: 0.764

Gnomad4 ASJ AF: 0.854

Gnomad4 EAS AF: 0.514

Gnomad4 SAS AF: 0.781

Gnomad4 FIN AF: 0.779

Gnomad4 NFE AF: 0.757

Gnomad4 OTH AF: 0.707

Alfa AF: 0.751 Hom.: 55074

Bravo AF: 0.694

Asia WGS AF: 0.650 AC: 2265 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 4 Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	This variant is associated with the following publications: (PMID: 28667701, 15026335, 20075119, 23273568, 21454826) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	14
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs34330; hg19: chr12-12870695; COSMIC: COSV57430533; COSMIC: COSV57430533;