12-12717638-C-T

Variant names:

• chr12-12717638-C-T
• rs183710253
• NM_004064.5:c.-202C>T

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.-202C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00612 in 1,466,776 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (8 hom., cov: 34)
  • Exomes 𝑓: 0.0062 (44 hom.)
• Consequence: CDKN1B NM_004064.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.274
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-12717638-C-T is Benign according to our data. Variant chr12-12717638-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 307656.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 = 0.00568 (865/152346) while in subpopulation NFE AF = 0.00704 (479/68030). AF 95% confidence interval is 0.00652. There are 8 homozygotes in GnomAd4. There are 466 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1B	NM_004064.5	c.-202C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 3	ENST00000228872.9	NP_004055.1
CDKN1B	NM_004064.5	c.-202C>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.-202C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 3	1	NM_004064.5	ENSP00000228872.4
CDKN1B	ENST00000228872.9	c.-202C>T		5_prime_UTR_variant	Exon 1 of 3	1	NM_004064.5	ENSP00000228872.4

Frequencies

GnomAD3 genomes AF: 0.00568 AC: 865 AN: 152228 Hom.: 8 Cov.: 34

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0251

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00704

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00617 AC: 8115 AN: 1314430 Hom.: 44 Cov.: 35 AF XY: 0.00594 AC XY: 3818 AN XY: 643110

African (AFR) AF: 0.000623 AC: 18 AN: 28914

American (AMR) AF: 0.00296 AC: 72 AN: 24314

Ashkenazi Jewish (ASJ) AF: 0.000732 AC: 15 AN: 20488

East Asian (EAS) AF: 0.00 AC: 0 AN: 35286

South Asian (SAS) AF: 0.000164 AC: 11 AN: 67160

European-Finnish (FIN) AF: 0.0239 AC: 730 AN: 30490

Middle Eastern (MID) AF: 0.00162 AC: 6 AN: 3694

European-Non Finnish (NFE) AF: 0.00667 AC: 6998 AN: 1049444

Other (OTH) AF: 0.00485 AC: 265 AN: 54640

GnomAD4 genome AF: 0.00568 AC: 865 AN: 152346 Hom.: 8 Cov.: 34 AF XY: 0.00625 AC XY: 466 AN XY: 74504

African (AFR) AF: 0.00113 AC: 47 AN: 41582

American (AMR) AF: 0.00287 AC: 44 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

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

European-Finnish (FIN) AF: 0.0251 AC: 267 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00704 AC: 479 AN: 68030

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00625 Hom.: 0

Bravo AF: 0.00407

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 4 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Jun 23, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.9
DANN	Benign	0.82
PhyloP100		-0.27
PromoterAI		0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
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: rs183710253; hg19: chr12-12870572;