12-12717574-C-G

Variant names:

• chr12-12717574-C-G
• rs3093728
• NM_004064.5:c.-266C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004064.5(CDKN1B):​c.-266C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,419,380 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0048 (22 hom.)
• Consequence: CDKN1B NM_004064.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.339
• Publications: 4 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]

CDKN1B Gene-Disease associations (from GenCC):

• multiple endocrine neoplasia type 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen
• multiple endocrine neoplasia

  Inheritance: AD Classification: STRONG Submitted by: G2P
• hereditary nonpolyposis colon cancer

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-12717574-C-G is Benign according to our data. Variant chr12-12717574-C-G is described in ClinVar as [Benign]. Clinvar id is 307654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0037 (564/152304) while in subpopulation NFE AF = 0.00566 (385/68026). AF 95% confidence interval is 0.00519. There are 2 homozygotes in GnomAd4. There are 261 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1B	NM_004064.5	c.-266C>G		5_prime_UTR_variant	Exon 1 of 3	ENST00000228872.9	NP_004055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1B	ENST00000228872.9	c.-266C>G		5_prime_UTR_variant	Exon 1 of 3	1	NM_004064.5	ENSP00000228872.4

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 564 AN: 152186 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00566

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.00482 AC: 6106 AN: 1267076 Hom.: 22 Cov.: 35 AF XY: 0.00478 AC XY: 2934 AN XY: 614272

African (AFR) AF: 0.000968 AC: 27 AN: 27890

American (AMR) AF: 0.00232 AC: 44 AN: 19006

Ashkenazi Jewish (ASJ) AF: 0.00514 AC: 95 AN: 18478

East Asian (EAS) AF: 0.00 AC: 0 AN: 33712

South Asian (SAS) AF: 0.00533 AC: 328 AN: 61540

European-Finnish (FIN) AF: 0.00128 AC: 36 AN: 28096

Middle Eastern (MID) AF: 0.000851 AC: 3 AN: 3524

European-Non Finnish (NFE) AF: 0.00523 AC: 5343 AN: 1022462

Other (OTH) AF: 0.00439 AC: 230 AN: 52368

GnomAD4 genome AF: 0.00370 AC: 564 AN: 152304 Hom.: 2 Cov.: 34 AF XY: 0.00351 AC XY: 261 AN XY: 74462

African (AFR) AF: 0.00144 AC: 60 AN: 41572

American (AMR) AF: 0.00346 AC: 53 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4820

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00566 AC: 385 AN: 68026

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00588 Hom.: 0

Bravo AF: 0.00352

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 4 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDKN1B: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		0.34
PromoterAI		0.043	Neutral
Mutation Taster		=300/0	polymorphism

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: rs3093728; hg19: chr12-12870508; COSMIC: COSV107211046;