12-12717638-C-T

Position:

• chr12-12717638-C-T

Variant summary

Our verdict is Benign. Variant got -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 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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.274

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=-0.88).
• 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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 865 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN1B	NM_004064.5	c.-202C>T		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.-202C>T		5_prime_UTR_variant	1/3	1	NM_004064.5	ENSP00000228872	P1

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

Gnomad4 AFR exome AF: 0.000623

Gnomad4 AMR exome AF: 0.00296

Gnomad4 ASJ exome AF: 0.000732

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.0239

Gnomad4 NFE exome AF: 0.00667

Gnomad4 OTH exome AF: 0.00485

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

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00287

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0251

Gnomad4 NFE AF: 0.00704

Gnomad4 OTH AF: 0.00236

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.9
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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: rs183710253; hg19: chr12-12870572;