12-12717714-C-T

Variant names:

• chr12-12717714-C-T
• rs549943001
• NM_004064.5:c.-126C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_004064.5(CDKN1B):​c.-126C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,559,008 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0017 (1 hom.)
• Consequence: CDKN1B NM_004064.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.11
• Publications: 0 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-12717714-C-T is Benign according to our data. Variant chr12-12717714-C-T is described in ClinVar as [Benign]. Clinvar id is 307657.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 = 0.00109 (166/152372) while in subpopulation NFE AF = 0.00184 (125/68034). AF 95% confidence interval is 0.00158. There are 0 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1B	NM_004064.5	c.-126C>T		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.-126C>T		5_prime_UTR_variant	Exon 1 of 3	1	NM_004064.5	ENSP00000228872.4

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152254 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000588

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.00168 AC: 2368 AN: 1406636 Hom.: 1 Cov.: 35 AF XY: 0.00162 AC XY: 1128 AN XY: 697454

African (AFR) AF: 0.000343 AC: 11 AN: 32116

American (AMR) AF: 0.000160 AC: 6 AN: 37404

Ashkenazi Jewish (ASJ) AF: 0.0000782 AC: 2 AN: 25580

East Asian (EAS) AF: 0.00 AC: 0 AN: 36850

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82182

European-Finnish (FIN) AF: 0.00216 AC: 77 AN: 35614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4090

European-Non Finnish (NFE) AF: 0.00201 AC: 2201 AN: 1094086

Other (OTH) AF: 0.00119 AC: 70 AN: 58714

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152372 Hom.: 0 Cov.: 34 AF XY: 0.00111 AC XY: 83 AN XY: 74512

African (AFR) AF: 0.000144 AC: 6 AN: 41596

American (AMR) AF: 0.000588 AC: 9 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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: 0.00184 AC: 125 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000858

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 4 Benign:2

Dec 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	13
DANN	Benign	0.78
PhyloP100		1.1
PromoterAI		0.023	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: rs549943001; hg19: chr12-12870648;